NO342745B1 - Inhibitors of E1-activating enzyme - Google Patents

Abstract

This invention relates to compounds which inhibit E1-activating enzymes, pharmaceutical compositions constituting the compounds, and methods of using the compounds. The compounds are useful for the treatment of disorders, especially cell proliferative disorders, including cancer, inflammatory and neurodegenerative conditions, and inflammation associated with infection and cachexia.

Description

O p<p>fmnation area

[001] This invention relates to chemical compounds, suitable for treating various disorders, in particular disorders associated with cell proliferation, including types of cancer as well as inflammatory disorders. Specifically, the description provides compounds that inhibit the activity associated with E1-type activating enzymes.

The background of the invention

[002] The post-translational modification of proteins by ubiquitin-like molecules (ubl's) is an important regulatory process inside cells and plays key roles in the control of many biological processes including cell division, cell signaling and immune response. Ubls are small proteins that are covalently linked to a lysine on a target protein via an isopeptide chain link with a C-terminal glycine on ubl. The ubiquitin-like molecule changes the molecular surface of the target protein and can affect properties such as protein-protein interactions, enzymatic activity, stability and cellular localization of the target.

[003] Ubiquitin and other ubl molecules are activated by a specific E1 enzyme that catalyzes the formation of an acyl-adenylate intermediate with the C-terminal glycine on ubl. The activated ubl molecule is then transferred to the catalytic cysteine residue concentration inside the E1 enzyme through the formation of a thioester binding intermediate. The E1-ubl intermediate and an E2 helper result in a thioester exchange in which ubl is transferred to the active site cysteine of E2. Ubl is then conjugated to the target protein either directly or in conjunction with an E3 ligase by means of an isopeptide bond formation with an amino group belonging to a lysine side chain in the target protein.

[004] The biological consequence of ubl modification depends on the target in question. Ubiquitin is the best described of the ubls and a consequence of modification through ubiquitination is the degradation of poly-ubiquitinated proteins by the 26S proteasomes. Ubiquitin is conjugated to its target proteins by an enzyme cascade involving its specific E1-activating enzyme, Ubal (ubiquitin-activating enzyme, UAE), a conjugating enzyme from the E2 family and a ubiquitin ligase from either the RING or HECT class associated with E3- is. See, Huang et ah, Oncogene. 23:1958-71 (2004). Target specificity is controlled through the particular combination of E2 and E3 protein, with >40 E2s and >100 E3s currently known. In addition to ubiquitin, there are at least 10 ubiquitin-like proteins, each of which is thought to be activated by a specific E1-activating enzyme and processed through similar but distinctive downstream conjugating methods. Other ubls in which E1-activating enzymes have been identified include Nedd8 (APPBPI-Uba3), ISG15 (UBE1L), and the SUMO family (Aosl-Uba2).

[005] Ubl-Nedd8 is activated through the heterodimeric Nedd8-activating enzyme (APPBP1-Uba3) (NAE) and transferred to a single E2 (Ubcl2) that ultimately results in ligation to cullin proteins. The function associated with the Nedd8 conjugation process consists of the activation of cullin-based ubiquitin ligases involved in the ubiquitination and consequently turnover of many cell cycle and

cell signaling proteins, including p27 and I-kB. See Pan et ah, Oncogene. 23:1985-97,

(2004). Ubl-SUMO is activated through the heterodimeric sumo-activating enzyme (Aosl-Uba2) (SAE) and transferred to a single E2 (Ubc9), followed by coordination with several E3 ligases, ultimately resulting in sumoylation of target proteins. SUMO modification can affect the cell localization of target proteins and proteins modified by SUMO family members are involved in nuclear transport, signal transduction and stress response. See Seler and Dejean, Nat Rev Mol Cell Biol. 4:690-9, (2003). The function associated with sumoylation includes the activation of cell signaling pathways (eg, cytokine, WNT, growth factor, and steroid hormone signaling) involved in transfer regulation in addition to pathways involved in the control of genome integrity (eg, DNA replication, response to DNA damage, recombination, and repair). See Muller et al, Oncogene. 23:1998-2006, (2004). There are other ubls (eg, ISG15, FAT 10, Apgl2p) whose biological functions are still under investigation.

[006] One particular method of importance that is regulated via E1-activating enzyme activities is the ubiquitin-proteasome pathway (UPP). As discussed above, the enzymes UAE and NAE regulate UPP during two different steps of the ubiquitination cascade. UAE activates ubiquitin during the first step of the cascade, while NAE, via activation of Nedd8, is responsible for the activation of the cullin-based ligases that are then necessary for the final transfer of ubiquitin to certain target proteins. A functional UPP method is necessary for normal cell maintenance. The UPP plays a central role in the turnover of many important regulatory proteins involved in transcription, cell cycle progression and apoptosis, all of which are important in disease states, including tumor cells. See, for example, King et al, Science 274:1652-1659 (1996), Vorhees et al, Clin. Cancer Res., 9:6316-6325 (2003) and Adams et al., Nat. Fox. Cancer, 4: 349-360 (2004). Proliferative cells are particularly sensitive to inhibition of the UPP. See, Drexler, Proe. Nati. Acad. Seal, USA 94: 855-860 (1977). The role of the UPP pathway in oncogenesis has led to the investigation of proteasome inhibition as a potential anticancer therapy. For example, modulation of the UPP pathway by inhibition of the 26S proteasome with VELCADE<®>(bortezomib) has been shown to be an effective treatment for certain cancers and is approved for the treatment of relapsed and refractory multiple myeloma. Examples of proteins whose levels are controlled by cullin-based ubiquitin ligases downstream of NAE and UAE activity include the CDK inhibitor p27K<ipl>and the NFkB-associated inhibitor, IkB. See, Podust et al, Proe. Nati. Acad. Sci., 97: 4579-4584, (2000), and Read et al., Mol. Cell Biol, 20: 2326-2333, (2000). Inhibition of degradation of p27 is expected to block the development of cells during the G1 and S phases of the cell cycle. Interference through degradation of IkB should prevent nuclear localization of NF-kB, transfer of various NF-kB-dependent genes associated with the malignant phenotype and resistance to standard cytotoxic therapies. In addition, NF-kB plays a key role in the expression of a number of pro-inflammatory mediators implicating a role for such inhibitors in the inflammatory diseases. In addition, inhibition of the UPP is included as a useful target for additional therapy, such as e.g. inflammatory conditions, including, for example, rheumatoid arthritis, asthma, multiple sclerosis, psoriasis and reperfusion injury, neurodegenerative conditions, including, for example, Parkinson's disease, Alzheimer's disease, triplet repeat conditions, neuropathic pain, ischemic conditions, for example, stroke, infarction , kidney disease and cachexia. See, for example, Elliott and Ross, Am J Clin Pathol.\\ 6:637-46 (2001), Elliott et al., J Mol Med. 81:235-45 (2003), Tarlac and Storey, J. Neurosci. Res. 74: 406-416 (2003), Mori et al, Neuropath. Appl. Neurobiol., 31: 53-61 (2005), Manning, CurrPain Headache Rep. 8: 192-8 (2004), Dawson and Dawson, Science 302: 819-822 (2003), Kukan, JPhysiolPharmacol. 55: 3-15 (2004), Wojcik and DiNapoli, Stroke. 35:1506-18 (2004), Lazarus et al., Am JPhysiol. 27:E332-41 (1999).

[007] By targeting E1-activating enzymes, one gets a unique opportunity to intervene with a number of biochemical methods that are important for maintaining the integrity of cell division and cell signalling. E1-activating enzymes function during the first step associated with ubl conjugation methods, and consequently inhibition of an E1-activating enzyme will definitely modulate the downstream consequences associated with ubl modification. In this way, inhibition of these activating enzymes and the resulting inhibition of the downstream effects associated with ubl conjugation represents a method to be able to intervene in the integrity associated with cell division, cell signaling and several aspects associated with cell physiology that are important for disease mechanisms. Accordingly, E1 enzymes such as UAE, NAE and SAE, as regulators of various cellular functions, are potentially important therapeutic targets for the identification of new methods for the treatment of diseases and disorders.

Description of the invention

[008] This invention provides chemical compounds. The compounds are useful for inhibiting E1 activity in vitro and in vivo and are useful for treating disorders associated with cell proliferation, particularly types of cancer and other disorders associated with E1 activity. The compounds associated with the invention have the general formula (I):

or a pharmaceutically acceptable salt thereof

stereochemical configurations drawn at positions with asterisks show relative stereochemistry,

Ring A is selected from the group consisting of:

where one ring nitrogen atom in ring A is optionally oxidized,

Ra is hydrogen or OH,

R<b>is hydrogen, fluoro or C1-4 aliphatic group,

R° is hydrogen, fluoro or OH

R d is hydrogen, fluoro or C 1-4 aliphatic group,

Re is hydrogen or C1-4 aliphatic group,

Re is hydrogen,

each Rf is hydrogen,

R<g>is hydrogen, halogen, -OR<5>, -SR<6>, -N(R<4>)2, -NR<4>C(0)R<5>or an optionally substituted

aliphatic group,

each Rh is hydrogen,

Rj is hydrogen,

R<k>is hydrogen or halogen,

each R<4> is independently hydrogen or an optionally substituted aliphatic, aryl, heteroaryl or heterocyclyl group,

each R<5> is independently hydrogen or an optionally substituted aliphatic, aryl, heteroaryl or heterocyclyl group,

each R<6> is individually an optionally substituted aliphatic, aryl or heteroaryl group,

and

m is 1, and

where the optional substituent is halogen, C1-4aliphatic group, C1-4alkyl, C1-4halogenaliphatic group, C1-4halogenalkoxy, phenyl, or phenyl substituted with halogen, C1-4aliphatic group, C1-4alkyl, C1-4halogenaliphatic group, C1-4 4halogenoalkyl.

A compound of formula (I) characterized by the following properties is preferred

(a) X is -O-,

(b) Y is -CH2-,

(c) Ra is -OH,

(d)R<b>and Rd are hydrogen,

(e) R° is hydrogen,

(f)Re and Re are each hydrogen,

(g) each Rf is hydrogen;

(h) each Rh is hydrogen,

(i) R<>>is hydrogen,

(j) R<k>is hydrogen,

(k) m is 1, and

(1) stereochemical configurations depicted as asterisked positions show absolute stereochemistry.

Another embodiment is compound of formula (I) characterized by formula

(VII) :

or a pharmaceutically acceptable salt thereof wherein: Q is =N or =C(R<k>)- where R<k> is hydrogen,

V<2> is -N(R<8>)-, -O- or -S-,

R<8> is hydrogen or C1-4 aliphatic, and

ring D is optional, a substituted mono-, bi- or tricyclic ring system wherein ring D is selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl, purinyl, quinolyl, isoquinolyl, quinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, quinuclidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, penanthridinyl, tetrahydronaphthyl, indolinyl, benzodioxanyl, cromanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclope ntenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, bicycloheptanyl and bicyclooctanyl, and

where the optional substituent is halogen, C 1-4 aliphatic group, C 1-4 alkoxy, C 1-4 haloaliphatic group, C 1-4 or halogeno alkoxy.

Preferred are the compounds of formula (VII) where ring D is optionally a substituted indanyl, tetrahydronaphthyl or chromanyl.

Further preferred are the compounds of formula (VII) where:

ring D is selected from the group consisting of:

each R<p>which is individually selected from the group consisting of halogen, -OR<5x>and a Ci-4

aliphatic group,

each R<8p>which is individually selected from the group consisting of fluoro, -OR<5x>, and a Ci-4

aliphatic group, provided that R<8P>is something other than -OR<5x>when located at a position adjacent to a ring oxygen atom and further provided that when two R<8P>s

attached to the same carbon atom, must be selected from the group consisting of fluoro, each R<5x>is optionally hydrogen or C1-4alkyl,

serO, 1,2,3 or 4,

t is 0, 1 or 2.

Another embodiment is a compound of formula (VII) characterized by formula (Villa):

or a pharmaceutically acceptable salt thereof wherein:

Ra is -OH,

R<b>and Rd are hydrogen,

R° is hydrogen, fluoro or OH,

R<8>is hydrogen,

Q is =N- or =C(R<k>) where R<k> is hydrogen,

each R<p> is individually selected from the group consisting of fluoro and -OR<5x>,

each R<8p> individually is selected from the group consisting of fluoro and -OR<5x>,

each R<5x> individually is hydrogen and C1-4 aliphatic group,

s is 0, 1 or 2, and

t is 0, 1 or 2.

Preferred are compounds of formula (I) where the compound is

Preferred is a compound of formula (I) which is

or a pharmaceutically acceptable salt thereof.

General synthetic methodology

[0109] The compounds associated with the present invention can be prepared using methods known to a person of ordinary skill in the art and/or by reference to the preparations shown below and the synthetic examples that follow. Examples of synthetic methods can be found in preparations 1 to 10 below as well as in the examples.

Preparation 1: General method for the synthesis of 4-substituted ((1S,2S,4R)-2-hydroxy-4-{7//-pyrrolo[2,3-(/]pyrimidin-7-yl}cyclopentyl)methylsulfamates

[0110] Preparation 1 above shows a general method for preparing compounds associated with formula (i) where ring A has formula A-ii. Persons of ordinary skill in the art will appreciate that compounds of formula (I) wherein ring A is different from A-ii can be prepared using the same general method starting with suitable starting materials analogous to i.

[0111] Methods for the synthesis of chloro-substituted pyrrolopyrimidines such as e.g. formula i, are known (P. Reigan et at., Bioorg. Med. Chem. Lett., 2004, 14, 5247-5250, J. Heterocyclic Chem., 1988, 25, 1633-1639). As shown in Preparation 1, conversion of compounds of formula I to substituted pyrrolopyrimidines is achieved by coupling with the appropriate substituted amines or mercaptans (see Pathak, A.K.; Pathak, V.; Seitz, L.E.; Suling, W.J.; Reynolds, R.C., J . Med. Chem. 2004, 47, 273-276) at elevated temperature in protic solvents, such as e.g. butanol or isopropanol, using a suitable base, such as e.g. DIPEA or Et3N (method A). As another alternative, pyrrolopyrimidines can be coupled with a suitable substituted alcohol in H2O where there is a base, such as e.g. KOH, at refluxing temperatures (method B). Compounds of formula i can also be treated with Grignard reagents in the presence of ferrous acetylacetonate in THF (Method C) to give carbon-substituted pyrrolopyrimidines. Compounds iv are prepared from ii through the opening of epoxide iii with a suitable base, such as e.g. NaH, LiHMDS or cesium carbonate, at elevated temperatures in DMF (method

D).

[0112] For the preparation of compounds related to formula (I) where R° and Rd are both hydrogen, deoxygenation can be effected during this stage. Accordingly, alkylation of compounds of formula iv to give xanthogenates v is effected by treatment with chlorophenylthiocarbonate and a suitable base, such as e.g. DMAP, in DCM (method E). Aboxygenation of compounds associated with formula v is achieved by treatment with a radical source, such as e.g. Bu3SnH and a radical initiator, such as e.g. AIBN, in refluxing toluene (method F). Subsequent deprotection with an aqueous acid, such as AcOH (method G), gives the compounds associated with formula vii.

[0113] The primary alcohol associated with the diols of formula vii is selectively protected, for example, with a large silyl protecting group such as TBDMS. Subsequent treatment with acid anhydride gives the protective alcohols associated with formula viii (method H). Selective deprotection of the primary alcohol using a fluoride reagent, such as pyridine hydrofluoride, in a basic solvent, such as pyridine, gives compounds related to formula ix (method I). Further treatment with newly prepared chlorosulfonamide x yields the penultimate sulfamates xi (method J). Acetate removal by treatment with a base, such as ammonia in MeOH according to by method K, gives compounds of formula xii.

Preparation 2: Alternative method in the synthesis of 4-7V-substituted ((1S,2S,4R)-2-hydroxy-4-{7i7-pyrrolo[2,3-βnpyrimidin-7-yl)cyclopentyl)methylsulfamates

[0114] Compounds related to formula (l) where R s is -N(R 4 ) 2 can be prepared by an alternative method where a later stage intermediate incorporates a group that is replaced or removed, such as e.g. a sulfone which is directly displaced by a substituted amine. As shown in preparation 2, treatment of the compounds associated with formula i with benzyl mercaptan under conditions described in method B yields benzylsulfanylpyrrolopyrimidine associated with formula xiii. Subsequent treatment with the conditions outlined in methods D-F gives compounds associated with formula xiv. The compounds xiv are reacted with an oxidizing agent, such as e.g. wj-CPBA, in DCM where there is a base, such as e.g. sodium bicarbonate, to give sulfones of formula xv (Method L).

[0115] Compounds of formula xvi are then synthesized by treating xv with a suitable substituted amine using a base, such as DIPEA, in a high-boiling protic solvent, such as EtOH, at elevated temperatures (method M) similar to literature procedures (Lin, X.; Robins, M.J., Organic Lett. 2000, 2, 3497-3499). Removal of the protecting group is achieved in a manner analogous to that shown in Preparation 1, using the procedure described in Method G, to give diols of formula xvii. Methods for the synthesis of tert-butylchlorosulfonylcarbamate xviii are known (Hirayama et al, Biorg. Med. Chem., 2002, 10, 1509-1523), and this reagent is selectively reacted with the primary alcohol using a hindered base, such as .ex. 2,6-di-te/t-butyl-4-methylpyridine, in a solvent, such as e.g. AcCN, to give Boe sulfamates of formula xix (Method N). TFA deprotection in accordance with Method O affords the compounds of formula xx. The conversion of compounds xv to xvi has the potential advantages of being amenable to solution phase library synthesis.

Preparation 3: Synthesis of substituted epoxides

[0116] Methods for the synthesis of the intermediate alkene diol xxi are known (Nucleosides, Nucleotides & Nucleic Acids, 2002, 21, 65-72). After treatment with m-CPBA, diol xxi is converted to epoxydiol xxvii. Subsequent protection of the diol using p-anisaldehyde dimethylacetal gives epoxy iii. Alternatively, TBDPS protection of the primary alcohol of xxi followed by PDC oxidation affords a,|3-unsaturated ketone xxii. Addition of MeLi to the ketone in ET2O gives tertiary alcohol xxiii, and treatment with TBAF in THF gives diol xxiv. Epoxidation and diol protection gives the protected substituted epoxide xxvi.

Preparation 4: General method for the synthesis of substituted aminoindane

[0117] The aminoindane used to prepare 4-aminoindanyl compounds associated with formula xxx are either commercially available or they are prepared through the literature methods highlighted in Preparation 4. Appropriately substituted indanones associated with xxviii are treated with (R)-2-amino-2-phenylethanol to give the desired intermediate imine. Subsequent reaction with a suitable reducing agent, such as e.g. sodium borohydride in which AcOH is present gives amino alcohols of formula xxix (method P). Treatment with lead tetraacetate, followed by reflux in HC1, gives the aminoindane of formula xxx (Method Q). One of skill in the art will appreciate that using (S)-2-amino-2-phenylethanol in method P can be used to give the opposite enantiomers of indane xxx.

Preparation 5: General method for the synthesis of 4-substituted ((1S,2S,4R)-2,3-dihydroxy-4-{7/7-pyrrolo[2,3-d]pyrimidin-7-yl} cyclopentyl)methylsulfamates

[0118] Compounds associated with formula (I) where R<c>-OR<5> can be prepared as outlined in preparation 5. Accordingly, the compounds associated with formula iv, as prepared in preparation 1, are converted directly to triols associated with formula xxxi (method G) . Protection of the two secondary alcohols with 2,2-dimethoxypropane and an acid catalyst, such as p-TSA monohydrate, in acetone gives the isopropylidene xxxii (Method R). Further reaction with chlorosulfonamide x using method J, as described in preparation 1, gives sulfamates associated with formula xxxiii. Removal of the isopropylidene using acid, such as TFA in the presence of water gives compounds of formula xxxiv (II-C) according to method S. Alternatively, triol xxxi can be selectively sulfamoylated at the primary hydroxyl as described in Preparation 2, Methods N-0 to give compounds of formula formula xxxiv.

Preparation 6: General method in the synthesis of 4-amino and 4-acylamino substituted ((1S,2S,4R)-2-hydroxy-4-[7JH-pyrrolo[2,3-</]pyrimidin-7-yl}- cyclopentyl)methylsulfamates

[0119] Compounds associated with formula xxxv are prepared using the methods described in preparation 1. Treatment of benzylamines xxxv with an aqueous acid, such as e.g. AcOH, gives amines xxxvi (Method G). Selective protection of the primary alcohol using TBDMSC1 and a suitable base, such as imidazole, in DMF gives compounds of formula xxxvii (method T). Bis-acylation is effected through treatment with a suitable substituted acylating reagent associated with formula xxxviii (X = Cl, OH, -OC(0)R<5>) and a suitable base, such as e.g. pyridine, to be able to give compounds related to formula xxxix (method U). Applying the conditions described in Methods I-K to compounds xxxix yields both the fully deprotected analogs xl and the amines xli.

Preparation 7: General method in the synthesis of -substituted ((1S,2S,4R)-4-{7//-pyrrolo-[2,3-</]pyrimidin-7-yl}cyclopentyl)methylsulfamates

[0120] Compounds associated with formula (l) where Ra and R<c>together form a bond and compounds associated with formula (I) where each of Ra-Rd is hydrogen can be prepared as outlined in preparation 7. Triols associated with formula xlii are prepared according to the method in Preparation 5. The primary alcohol is selectively protected to give the diols associated with formula xliii (Method T), which are then alkylated by 1,1-thiocarbonyldiimidazole in a suitable solvent, such as e.g. DMF, to give dioxol ions xliv (Method U). Treatment with 1,3-dimethyl-2-phenyl-1,3,2-diazaphopholidin in a suitable solvent, such as e.g. THF, gives the alkenes of formula xiv (method V), which are subjected to the conditions outlined in methods I-J to give sulfamates xlvi. Hydrogenation under a hydrogen atmosphere where there is a catalyst, such as e.g. palladium on carbon in EtOAc gives saturated sulfamates of formula xlvii (Method W).

Preparation 8: Synthesis of 5-fluoro pyrrolo[2,3-</]pyrimidines

[0121] Compounds related to formula (l) where R<k>is other than hydrogen are prepared as outlined in Preparations 8 and 9. Conversion of i to fluorochloropyrrolopyrimidine xlvii is carried out by treatment with Selectfluor™ (1-chloromethyl-4-fluoro-l ,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) and AcOH in AcCN. Compound xlviii is then substituted with the suitable substituents according to method A-C and transferred to compounds associated with formula (I) in accordance with preparation 1.

Preparation 9: Alternative method to 4,5-disubstituted ((1S,2S,4R)-2-hydroxy-4-{7/7-pyrrolo-[2,3-rf]pyrimidin-7-yl}cyclopentyl)methylsulfamates

[0122] Compounds associated with formula xlix are prepared as shown in preparation 1 and converted to iodide 1 by treatment with NIS (method X). Iodide 1 can be converted to compounds of formula li using various palladium-catalyzed coupling conditions, such as Sonagashira coupling (Cul, PdCh(PPh3)2, D1PEA, R'C=CH, Method Y). After the methods shown in preparation 1 are followed, the compounds associated with formula li are converted to final compounds associated with formula (/).

Preparation 10: Synthesis of ((2S,3S,4R,SR)-5-(4-(alkylamino)-7i/-pyrrolo[2,3-</]pyrimidin-7-yl)-3,4-dihydroxy- tetrahydrofuran-2-yl)methylsulfamates

[0123] Compounds associated with formula (/) where Y is -O- can be prepared from compounds lviii. The synthesis associated with the compounds of formula lviii is referred to in the literature (Ugarkar, B.G.; Castellino, AJ.; DaRe, J.S.; Ramirez-Weinhouse, M.; Kopcho, J.J.; Rosengren, S.; Erion, M.D., J. Med. Chem. , 2003, 46, 4750-4760) and is outlined in preparation 10. Methods for the conversion of D-ribose to lii are known (Inokawa, S.; Kitagawa, H.; Seo, K.; Yoshida, H.; Ogata, T., Carbohydr. Hydr. Res., 1973, 30, 127-132). Hydroboration-oxidation using borane THF complex gives liii which is globally deprotected with sulfuric acid. Tetraol liv is protected using 2,2-dimethoxypropane and subsequent protection of the primary alcohol using TBDMS-C1 gives alcohol lvi. Selective chlorination using CCU and HMPT in toluene gives the single enantiomer lvii. Glycosylation using compounds associated with formula i gives intermediates associated with formula lviii which can be further elaborated as e.g. described in preparation 1, 2 and 6 above. Preparation 11: Synthesis of 2-((1S,2S,4R)-4-4-[(1S)-2,3-dihydro-1#-inden-1- ylaminol-7//-pyrrolo [2,3-*/] pyrimidin-7-yl-2-hydroxycyclopentyl) ethanesulfonamide

[0124] Compounds related to formula (I) where X is CFhkan are prepared from compounds vii. As shown in Preparation 11, diol vii is protected as a bis-TBDMS ether lix using TBDMS-C1, suitable base, such as triethylamine and 4-DMAP (method Z). Selective deprotection of primary TBDMS group to lx is done using aqueous acid at elevated temperature (method AA). Aldehyde lxi is obtained by oxidizing alcohol lx using TPAP and a suitable oxidant, such as e.g. NMO (method AB). Treatment of aldehyde lxi with (diethoxyphosphoryl)-methanesulfonic acid ethyl ester and red-BuLi (method AC) gives alkene lxii which is then reduced to sulfonyl ester lxiii using a suitable reducing agent, such as e.g. sodium borohydride in ethanol (method AD). Hydrolysis of the former ester using TBAI under microwave conditions (method AE) yields sulfonic acid lxiv which is converted to protected sulfonamide lxv via intermediate sulfonyl chloride

(using thionyl chloride and then ammonia in dioxane, method AF). TBDMS deprotection using a suitable reagent, such as TBAF in THF (Method AG) gives sulfonamide lxvi.

Preparation 12: Synthesis of (£)-2-((1S,2S,4R)-4-(4-[(1S)-2,3-dihydro-1#-inden-1-ylamino]-7/Z- pyrrolo[2,3-*/]pyrimidin-7-yl}-2-hydroxycyclopentyl)ethylenesulfonamide

[0125] Compounds associated with formula (I) where X is -CH= can be prepared from compounds lxi. Like for example. shown in Preparation 12, tert-butyl([(diphenylphosphoryl)methyl]sulfonyl}carbamate is treated with r-BuLi and the resulting reagent is mixed with aldehyde lxi (Method AH) to afford protected vinylsulfonamide lxvi. The Boc group is deprotected using of a suitable Lewis acid such as ZnBn (Method AI) to give lxvii The final deprotection of a TBDMS group is carried out using a suitable reagent such as TBAF in THF (Method AJ ), to give lxviii.

Preparation 13: General method for 4-substituted ((1S,2S,4R)-2-hydroxy-4-(7//-pyrrolo[2,3-</|-pyrimidin-7-yl}cyclopentyl)methylsulfamides

[0126] Compounds associated with formula (/) where X is NH can be prepared from compounds lx. As shown in preparation 13, alcohol 1x is treated with A 2 -Boc-sulfonamide under Mitsunobu conditions, which e.g. triphenylphosphm and EAD in ethyl acetate under elevated temperature to be able to give sulfamide lxix (method AK). The TBDMS group is deprotected using a suitable acid, such as e.g. aqueous HC1 (method AL) to give lxx. The final deprotection of a Boc group is carried out using a suitable reagent, such as e.g. TFA in methylene chloride (Method AM) to give lxxi.

Preparation 14: General method by 4-substituted ((1S,2S,4R)-2-hydroxy-4-{7//-pyrrolo[2,3-</]-pyrimidin-7-yl}cyclopentyl)methyl N- methylsulfamides

[0127] Compounds related to formula (i) where X is -N(CH3)- can be prepared from compounds lxix. As shown in Preparation 14, sulfamide lxix is reduced with a suitable reagent, such as LiAlFLt in THF under elevated temperature to give protected N-methylsulfamide lxxii (method AN). The TBDMS group is deprotected using a suitable acid such as e.g. aqueous HC1 (method AL) to give lxxiii.

Preparation 15: Synthesis of ((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[4-[(1S)-2,3-dihydro-1/-indene -1-ylamino}-7H-pyrrolo[2,3-E?]pyrimidin-7-yl)cyclopentyl)methylmethanesulonate

[0128] Compounds associated with formula (I) where X is O and m = 2 can be prepared from compounds lx. As shown in preparation 15, alcohol lx is converted to a suitable group which is replaced or removed, such as mesylate lxxix, using methanesulfonyl chloride and a suitable base, such as e.g. triethylamine in DCM (method AO). The mesylate formed is rearranged with a nitrile group using a suitable nucleophile, such as e.g. sodium cyanide in DMSO under elevated temperature (method AP) to be able to give nitrile lxxx which is reduced to aldehyde lxxxi using a suitable reducing agent, such as e.g. DIBAL in DCM (method AQ). Further reduction of lxxxi using a suitable reagent, such as e.g. sodium tetrahydroborate in methanol gives alcohol lxxxii (Method AR). Treatment of lxxxii with a sulphating reagent, such as chlorosulfonamide in acetonitrile where there is a suitable base, such as e.g. triethylamine, gives protected sulfamate lxxxiii (Method J). TBDMS removal by treatment with an acid, such as HF. pyridine, in pyridine/THF acc. method AS, gives compounds associated with formula lxxxiv.

Preparation 16: Synthesis of Diastereoisomer Mixture of (1S,2R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo [2, 3-rf]pyrimidin-7-yl]-2-hydroxycyclopentylsulfamate and (1R,2S,4S)-4-[4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]- 7/-pyrrolo[2,3<f|pyrimidin-7-yl}-2-hydroxycyclopentylsulfamate

[0129] Compounds associated with formula (I) where X is O and m = 0 can be prepared from 3-cyclopenten-1-ol (lxxxv). As shown in Preparation 16, alcohol lxxxv is activated by conversion to a suitable group that is replaced or removed, such as mesylate lxxxvi using ethanesulfonyl chloride and a suitable base, such as e.g. pyridine and AP in DCM (method AT). Treatment of mesylate lxxxvi with base lxxxvii in which cesium carbonate is present in DMF under elevated temperature (method AU) gives lxxxviii. Treatment of alkene lxxxviii with a suitable chiral dihydroxylating agent, such as e.g. AD-nnix-a (Sigma-Aldrich) in tert-butyl alcohol (method AV) gives diol lxxxix which, after sulfation with chlorosulfonamide as described in method J, gives a diastereoisomer mixture of sulfamates xc and xci (method AW).

[0130] The description additionally provides synthetic intermediates which are useful in the preparation of the compounds associated with formula (I). In one embodiment, the invention provides a composition associated with formula (IX):

there:

stereochemical configurations are shown showing absolute stereochemistry,

Rb is fluoro, C1-4 aliphatic or C1-4 fluoroaliphatic,

R<aa>and R<bb>are each hydrogen or a hydroxyl protecting group or where R<aa>and R<bb>together form a cyclic diol protecting group, and

the variables Rd, Re and Rf have the values and the preferred values described above for formula (I).

[0131] As used herein, the term "hydroxyl protecting group" refers to a chemical group that i) reacts with a hydroxyl functional group of a substrate to be able to form a protective substrate ii) is stable against the reaction conditions to which the protected substrate is subjected and iii) can be removed for a protected substrate to release the hydroxyl functionality gap under conditions compatible with other functionality present in the substrate. Hydroxyl groups on 1,2- and 1,3-diols may be individually protected or may be jointly protected by a cyclic protecting group. Examples of suitable hydroxyl protecting groups are found in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons Inc., NY (1999).

[0132] In a specific design, the compound associated with formula (VIII) is represented by the formula:

[0133] The invention is also produced as a compound of formula (X):

there:

stereochemical configurations are shown showing absolute stereochemistry,

R<aa>is hydrogen or a hydroxyl protecting group, and R<bb>is hydrogen or a hydroxyl protecting group, or R<a>a and Rb<b>which together form a cyclic diol protecting group, and

the variables R<b>, Rd, Re and Rf have the values and the preferred values described above for formula (I).

[0134] In one embodiment, the compound is associated with formula (X), characterized by formula (Xa):

where Ar is, if chosen, a substituted aryl group. In some embodiments, Ar is optionally a substituted phenyl group. In certain embodiments, Ar is para-methoxy-phenyl.

[0135] In certain embodiments, the compound associated with formula (Xa) is selected from the group consisting of:

where Ar is as described above for formula (Xa).

[0136] The invention is also produced as a compound associated with formula ( XI ) or formula ( XII ).

there:

stereochemical configurations are shown showing absolute stereochemistry,

R<a>a is hydrogen or a hydroxyl protecting group, and

R<bb>is hydrogen or a hydroxyl protecting group,

R<cc>is hydrogen or a hydroxyl protecting group, or

R<aa>and R<bb>which together form a cyclic diol protecting group, or

R<a>a and Rccwhich together form a cyclic diol protecting group, and

Ring A and the variables R<b>, Rd, Re and Rf have the values and the preferred values described above for formula (i).

[0137] In some embodiments, the compound is characterized by formula (Xla) or

(Xlla)

[0138] In certain embodiments, the invention is associated with a compound selected from the group consisting of:

[0139] In certain other embodiments, the invention is associated with a compound selected from the group consisting of:

whereRaa and R<c>each individually is a hydroxyl protecting group or R<aa>and Rcc which together form a cyclic diol protecting group.

[0140] In certain other embodiments, the invention is associated with a compound selected from the group consisting of:

derRaa and R<bb>are each a hydroxyl protecting group. In some designs, Raa and Rbb are chosen to be able to provide selective protection and shielding. In certain embodiments, Raa is an acyl protecting group, and Rbber is a silyl protecting group. In a particular embodiment, R<aa> is acetyl or substituted acetyl, and Rbb is tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

Areas of use for compounds associated with the invention

[0141] The compounds associated with this disclosure are practical inhibitors of E1 enzyme activity. Specifically, the compounds are designed to be inhibitors of NAE, UAE, and/or SAE. The inhibitors are intended to include compounds that reduce the activating effects of the E1 enzymes in ubl conjugation to target proteins (eg, reduction of ubiquitination, Nedd8 conjugation process, sumoylation), reduce intracellular signaling mediated by ubl conjugation, and /or reduce proteolysis mediated by ubl conjugation (eg, inhibition of cullin-dependent ubiquitination and proteolysis (eg, the ubiuitin-proteasome pathway)). Accordingly, the compounds associated with this invention can be analyzed for the ability to inhibit the E1 enzyme in vitro or in vivo or in cells or animal models according to methods which are prepared in more detail herein or methods which are known in the art. The compounds can be assessed for their ability to bind or mediate E1 enzyme activity directly. Alternatively, the compounds' activity can be assessed through indirect cell assays or assays of the downstream effects of E1 activation to assess inhibition of downstream effects of E1 inhibition (eg, inhibition of cullin-dependent ubiquitination and proteolysis). Activity can, for example, be assessed by detection of ubl-conjugated substrates (eg, ubl-conjugated E2s, Nedd8-conjugated cullins, ubiquitinated substrates, sumoylated substrates), detection of downstream protein substrate stabilization (eg, stabilization of p27, stabilization of IkB), detection of inhibition of UPP activity, detection of downstream effects on protein E1 inhibition and substrate stabilization (eg, reporter assays, eg, NFkB reporter assays, p27 reporter assays). Analyzes to assess activities are described below in the experimental section and/or are known in the art.

[0142] One embodiment of this invention relates to a composition that includes a compound of this invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. It will be understood that the compounds associated with this disclosure can be derivatized by functional groups to provide prodrug derivatives which can be converted back to the parent compounds in vivo. Examples of such prodrugs include the physiologically acceptable and metabolically labile ester derivatives, such as e.g. methoxymethyl esters, methylthiomethyl esters or pivaloyloxymethyl esters derived from a hydroxyl group attached to the compound or a carbamoyl moiety derived from an amino group of the compound.

[0143] If pharmaceutically acceptable salts associated with the compounds of the invention are used in these compositions, the salts are preferably derived from inorganic or organic acids and bases. For review of suitable salts, see, for example, Berge et al, J. Pharm. Pollock. 66:1-19 (1977) and Remington: The Science and Practice of Pharmacy, 20th Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000.

[0144] Examples of suitable acid addition salts include the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate , hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate , tosylate and undecanoate.

[0145] Suitable base addition salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as e.g. Dicyclohexylamine salts, N-methyl-D-glucamine and salts with amino acids such as arginine, lysine and so on.

[0146] In some embodiments, the invention relates to an acid addition salt of a compound of formula / formed by protonation of a basic moiety in the molecule. In certain embodiments, this invention relates to a hydrochloride salt of the compound of formula /.

[0147] In some other embodiments, the invention relates to a basic addition salt of the compound associated with formula / formed by proton loss of the sulfamate (X = O) moiety, sulfamide (X = NH) moiety or sulfonamide (X = CEh) moiety, as applicable . In some such embodiments, the invention is associated with a sodium or potassium salt of the compound associated with formula /.

[0148] In addition, nitrogen-containing basic groups can be converted to quaternary compounds by such agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides, dialkyl sulphates, such as dimethyl, diethyl, dibutyl and diamyl sulphates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as e.g. benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thus obtained.

[0149] The term "pharmaceutically acceptable carrier" is used here to refer to a material that is compatible with a recipient subject, preferably a mammal and most preferably a human, and is suitable for delivering an active agent to a target site without interrupting the agent's activity. Any toxicity or negative effects associated with the carrier preferably correspond to a reasonable benefit-risk ratio for the intended use of the active agent.

[0150] The pharmaceutical compositions associated with the description can be prepared by methods that are well known in the art such as e.g. conventional granulation, mixing, dissolution, encapsulation, lyophilization or emulsification processes, among others. The compositions may be prepared in various forms, including granules, precipitates or particles, powders, including freeze-dried, spin-dried or spray-dried powders, amorphous powders, tablets, capsules, sugar solutions, suppositories, injections, emulsions, elixirs, suspensions or solutions. Formulations may, if chosen, contain stabilizers, pH mixing materials, surfactant pills, alkalizing agents, biologically available mixing materials and combinations thereof.

[0151] Pharmaceutically acceptable carriers that can be used in these compositions include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates or carbonates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as e.g. protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool grease.

[0152] According to a preferred design, the compositions in this description are formulated for pharmaceutical administration to a mammal, preferably a human. Such pharmaceutical compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intraperitoneal, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion technologies. Preferably, the compositions should be administered orally, intravenously or subcutaneously. The formulations associated with the description can be designed to be short-acting, fast-acting or long-acting. In addition, the connections can be managed locally instead of systemically, such as administration (eg, by injection) at a tumor site.

[0153] Pharmaceutical formulations can be prepared as liquid suspensions or solutions using a liquid, such as, but not limited to, an oil, water, an alcohol and combinations thereof. Alkalizing agents such as e.g. cyclodextrins may be included. Pharmaceutically suitable surfactants, suspending agents or emulsifying agents may be added for oral or parenteral administration. Suspensions may include oils such as, but not limited to, peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. Suspension preparations can also consist of esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as poly(ethylene glycol), petroleum hydrocarbons such as e.g. mineral oil and petrolatum, and water can also be used in suspension formulations.

[0154] Sterile injectable forms of the compositions associated with this description may be aqueous or oily suspensions. These suspensions can be formulated according to methods known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable binders and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, solid oils are usually used as a solvent or suspending agent. For this purpose any mild fixed oil can be used including synthetic mono- or di-glycerides. Fatty acids, such as Oleic acid and its glyceride derivatives are useful for the preparation of injectables in addition to natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also consist of a long-chain alcohol diluent or spraying agent, such as e.g. carboxymethylcellulose or sprays commonly used in formulations of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans, and other emulsifiers or bioavailable enhancers commonly used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation. The compounds may be formulated for parenteral administration by injection by bolus injection or continuous infusion. A unit dosage form for injection may be in ampoules or in multi-dose containers.

[0155] The pharmaceutical compositions associated with this disclosure may be administered orally in any orally acceptable dosage form including capsules,

tablets, aqueous suspensions or solutions. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweeteners, flavorings or coloring agents may also be added. For oral administration in a capsule form, useful diluents include lactose and dry corn starch. In the case of tablets for oral use, carriers such as lactose and corn starch are usually used. Lubricants, such as magnesium stearate, is also usually added. Coatings can be used for a variety of purposes, for example, to mask a taste, to affect a dissolution or absorption area or to prolong the drug's effect. Coatings can be applied to a tablet or to granulated particles to be used in a capsule.

[0156] As another alternative, the pharmaceutical compositions associated with this description can be administered in the form of suppositories for introduction through the rectum. These can be prepared by mixing the agent with a suitable non-irritating binder which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0157] The pharmaceutical compositions associated with this disclosure may also be administered locally, particularly when the focus of treatment includes areas or organs readily accessible by local administration, including eye or skin diseases or the lower part of the digestive tract. Suitable local formulations are easy to prepare for each of these areas or organs.

[0158] Local application in the lower part of the digestive tract can be carried out with a rectal suppository formulation (see above) or in a suitable enema formulation. Local transdermal patches can also be used. For local application, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component either suspended or dissolved in one or more carriers. Carriers for topical administration in the compounds of this invention include mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, pharmaceutical compositions may be formulated in a suitable cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0159] For use on eyes, the pharmaceutical compositions can be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline or preferably, as solutions in isotonic, pH-adjusted sterile salt, either with or without a preservative such as e.g. benzylalkonium chloride. As another alternative, for eye use, the pharmaceutical compositions can be formulated in an ointment such as petrolatum.

[0160] The pharmaceutical compositions associated with this disclosure may also be administered through the nose by aerosol or inhalation. Such compositions are prepared according to methods well known in the art associated with pharmaceutical formulation and can be prepared as solutions in salt water, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance biological availability, fluorocarbons, and/or other conventional dissolving or spraying agents.

[0161] The pharmaceutical compositions associated with this disclosure are particularly useful in therapeutic applications dealing with disorders as described herein (eg, proliferative conditions,/eg, cancer, inflammation, neurodegenerative conditions). Preferably, the composition is formulated for administration to a patient who already has or is at risk of developing or having a relapse of the relevant condition being treated. The term "patient" as used herein refers to an animal, preferably a mammal and most preferably a human. Preferred pharmaceutical compositions associated with the disclosure are those formulated for oral, intravenous or subcutaneous administration. However, any of the above dosage forms which provide a therapeutically effective amount of the compound will be well within the realm of routine experimentation and therefore well within the scope of the instant disclosure. In certain embodiments, the pharmaceutical composition of the description may additionally consist of another therapeutic agent. Preferably, the second therapeutic agent is usually administered to patients with the disorder, disease or condition being treated.

[0162] By "therapeutically effective amount" is meant an amount of a compound or compositions that is sufficient, after single or multiple dose administration, to produce a noticeable increase in E1 enzyme activity and/or the severity associated with the disorder or disease being treated. "Therapeutically effective amount" is also intended to include an amount sufficient to treat a cell, prolong or prevent further development of the disorder or disease phase being treated (eg, prevent additional growth of tumors associated with a cancer, prevent additional inflammatory response), improve , alleviate, alleviate or improve a person's symptoms associated with a disorder other than what would be expected without such treatment. The amount of E1 enzyme inhibitor required depends on the particular compound of the composition being administered, the type of disorder being treated, the method of administration, and the length of time needed to treat the disorder. It should also be understood that a particular dose and treatment regimen for any particular patient is dependent on a variety of factors, including the activity of the particular compound employed, age, body weight, general health, sex and diet of the patient, time of administration, rate of excretion , drug combinations, the judgment of the attending physician and the severity of the particular disease being treated. In certain embodiments where the inhibitor is administered in combination with another agent, the amount of additional therapeutic agent present in a composition associated with this disclosure is generally no more than the amount typically administered in a composition containing the therapeutic agent as the sole active agent. The amount of additional therapeutic agent is preferably from approx. 50% to approx. 100% of the amount normally present in a composition containing that agent as the sole therapeutically active agent.

[0163] A design of the description is associated with a method for inhibiting or reducing E1 enzyme activity in a sample which consists in making contact with a compound of this invention or composition which constitutes a compound of the invention. This sample, as used herein, includes a sample comprising purified or partially purified E1 enzyme, cultured cells or extracts of cell cultures, cells that have been biopsied or fluid from a mammal or extracts thereof as well as body fluid (eg, blood, serum , saliva, urine, faeces, semen, tears) or extracts thereof. Inhibition of E1 enzyme activity in a sample can be carried out in vitro or in vivo, in cellulo or in situ.

[0164] In another embodiment, the description provides a method for treating a patient with a disorder, a symptom of a disorder, with a risk of developing or having a relapse of a disorder wherein the method involves administering a compound or a pharmaceutical composition according to the description. Treatment can mean curing, curing, alleviating, easing, changing, fixing, improving, dulling, ameliorating or influencing the disorder, the symptoms associated with the disorder or predisposition to the disorder. While not wishing to be bound by theory, it is believed that treatment will cause inhibition of growth, removal or destruction of a cell or tissue in vitro or in vivo or otherwise reduce the capacity of a cell or tissue (eg, an abnormal cell, a diseased tissue) to convey a condition, for example, a condition as described herein (for example, a proliferative condition, for example, a cancer, an inflammatory condition). As used herein, "inhibiting the growth" or "inhibition of growth" of a cell or tissue (eg, a proliferative cell, tumor tissue) refers to the delay, interruption, arrest, arrest of growth and metastasis and does not necessarily indicate complete elimination of growth .

[0165] Areas of application for diseases according to the description include those conditions where inhibition of E1 enzyme activity has an adverse effect on the survival and/or expansion of disease cells or tissues (for example, the cells are sensitive to E1 inhibition, inhibition of E1 activity interferes with disease mechanisms , reduction of E1 activity stabilizes proteins that are inhibitors of disease mechanisms, reduction of E1 activity results in inhibition of proteins that are activators of disease mechanisms). Disease scopes are also intended to include any condition, disease or disorder requiring efficient cullin and/or ubiquitination activity where this activity can be regulated by reducing E1 enzyme activity (eg, NAE, UAE activity).

[0166] Methods associated with the disclosure are, for example, useful for treating disorders involving cell proliferation, including conditions that require an efficient cullin-dependent ubiquitination and proteolysis pathway (eg, the ubiquitin-proteasome pathway) for maintenance and/or progression of the disease state. The methods in the description are useful for treating conditions mediated via proteins (for example, NFkB activation, s27<Kip->activation, s21<WAF/clpl->activation, p53 activation) that are regulated by E1 activity (for example, NAE activity, UAE activity, SAE activity). Relevant conditions include proliferative conditions, especially cancer and inflammatory conditions (eg, rheumatoid arthritis, inflammatory bowel disease, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, dermatosis (eg, atopic dermatitis, psoriasis), vascular proliferative conditions (eg, atherosclerosis , restenosis) autoimmune diseases (for example, multiple sclerosis, tissue and organ rejection)) in addition to inflammation in connection with infection (for example, immune responses), neurodegenerative conditions (for example, Alzheimer's disease, Parkinson's disease, motor neuron diseases, neuropathic pain, "triplet repeat" conditions, astrocytoma and neurodegeneration as a result of liver disease caused by alcohol), ischemic damage (for example, stroke) and cake ski (for example, accelerated muscle protein breakdown that accompanies various physiological and pathological conditions, (for example, nerve damage, fasting, fever, acidosis, HIV infection ion, cancer and certain endocrinopathies)).

[0167] The compounds and pharmaceutical compositions in the description are

particularly useful in the treatment of cancer. As used herein, the term "cancer" refers to a cellular condition characterized by uncontrolled or unregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites. The term "cancer" includes solid tumors and blood-borne tumors. The term "cancer" includes diseases of the skin, tissues, organs, bones, cartilage, blood and veins. The term "cancer" also includes primary and metastatic cancer.

[0168] In some embodiments, the cancer is a solid tumor. Examples of solid tumors that can be treated by the methods of the disclosure include pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, including metastatic breast cancer, prostate cancer, including androgen-dependent and androgen-independent prostate cancer, renal cancer, including, for example, metastatic renal cell carcinoma, hepatocellular cancer, lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC) and lung adenocarcinoma, ovarian cancer, including, for example, progressive epithelial or primary peritoneal cancer, cervical cancer, stomach cancer, esophageal cancer, head cancer and neck, including, for example, head and neck squamous cell carcinoma, melanoma, neuroendocrine cancer, including metastatic neuroendocrine tumor, brain tumor, including, for example, glioma, adult anaplastic astrocytoma, adult glioblastoma multiforme, and adult anaplastic astrocytoma, bone cancer and soft tissue sarcoma.

[0169] In some other embodiments, the cancer is hematologically malignant Examples of hematologically malignant cancer include acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), including proliferative CML and CML blast phase (CML-BP), acute lymphoblastic leukemia (ALL) , chronic lymphocytic leukemia (CLL), Hodgkin's disease

(HD), non-Hodgkin's lymphoma (NHL), including follicular lymphoma as well as mantle cell lymphoma, B-cell lymphoma, T-cell lymphoma, multiple myeloma (MM), Waldenstrom's macroglobulinemia, myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with side blasts with ring (RARS), (refractory with excess blasts (RAEB) and RAEB in transformation (RAEB-T) and myeloproliferative syndromes.

[0170] In some embodiments, the compound or composition associated with the disclosure is used to treat a patient suffering from or at risk of developing or having a recurrence of a cancer selected from the group consisting of colorectal cancer, ovarian cancer, lung cancer, breast cancer , stomach cancer, prostate cancer and pancreatic cancer. In certain preferred embodiments, the cancer is selected from the group consisting of lung cancer, colorectal cancer, ovarian cancer, and a hematologic cancer.

[0171] Depending on the particular condition or disorder to be treated, the E1 enzyme inhibitor is administered in some embodiments in conjunction with other therapeutic agents. In some embodiments, additional therapeutic agents are those commonly administered to patients with the condition or disorder being treated. As used herein, the additional therapeutic agents typically administered to treat a particular condition or disorder are known as: "Suitable for the condition or disorder being treated."

[0172] The E1 inhibitor associated with the disclosure may be administered with the other therapeutic agent in a single dosage form or a separate dosage form. When administered as a separate dosage form, the second therapeutic agent may be administered before, concurrently, or after administration of the E1 inhibitor associated with the disclosure.

[0173] In some embodiments, the E1 enzyme inhibitor in the description is administered in conjunction with a therapeutic agent selected from the group consisting of cytotoxic agents, radiotherapy and immunotherapy suitable for the treatment of proliferative conditions and cancer. Examples of cytotoxics suitable for use in combination with E1 enzyme inhibitors in the disclosure include: antimetabolites, including, for example, capecitibine, gemcitabine, 5-fluorouracil or 5-fluorouracil/leucovorin, fludarabine, cytarabine, mercaptopurine, thioguanine, pentostatin and methotrexate , topoisomerase inhibitors, including, for example, etoposide, teniposide, camptothecin, topotecan, irinotecan, doxorubicin and daunorubicin, ulna alkaloids, including, for example, vincristine and vinblastine, taxanes, including,/or example, paclitaxel and docetaxel, platinum agents, including , for example, cisplatin, carboplatin and oxaliplatin, antibiotics, including, for example, actinomycin D, bleomycin, mitomycin C, adriamycin, daunorubicin, idarubicin, doxorubicin and pegylated liposomal doxorubicin, alkylating agents such as e.g. melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, and cyclophosphamide, including, for example, CC-5013 and CC-4047, protein tyrosine kinase inhibitors, including, for example, imatinib mesylate and gefitinib proteasome inhibitors, including, for example, bortezomib, thalidomide and related analogs, antibodies, including, for example, trastuzumab, ritukdimab, cetuximab and bevacizumab, mitoxantrone, dexamethasone, prednisone and temozolomide.

[0174] Other examples of agents with which the inhibitors associated with the description can be combined include anti-inflammatory agents such as e.g. corticosteroids, TNF-blockers, II-1 RA, azathioprine, cyclophosphamide and sulfasalazine, immunomodulatory and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, methotrexate and sulfasalazine, antibacterial and antiviral agents, and agents for the treatment of Alzheimer's such as e.g. donepezil, galantamine, memantine and rivastigmine.

[0175] So that this invention can be fully understood, the following preparatory and testing examples are presented.

EXAMPLES

Abbreviations

Analytical LC-MS methods

(0176) Spectra were run on a Phenominex Luna 5um Cl 8 50 x 4.6 mm column on a Hewlett-Packard HP1100 at 2.5 mL/min for 3 minutes using the following gradients: Formic acid standard (FA standard) : Acetonitrile containing zero to 100 percent 0.1% formic acid in water.

Ammonium acetate standard (AA standard): acetonitrile containing zero to 100 percent 10 mM AA in water.

Example 1: ((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-^-pyrimidine -7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-35)

Step a: (1R,2R,3S,5S)-3-(Hydroxymethyl)-6-oxabiscyclo[3.1.0]hexan-2-ol

[0177] (1S,5S)-5-(Hydroxymethyl)cyclopent-2-en-1-ol (3.19 g, 27.9 mmol) was dissolved in DCM (143 mL) and the solution was cooled to 0 °C . 3-Chloroperbenzoic acid (7.52 g, 33.5 mmol) was added and the mixture was stirred at room temperature for 4 hours. TLC showed complete conversion. Silica gel (20g) was added, the mixture was concentrated to dryness and was purified via silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in DCM to give the title compound (2.75g, 76%). LC/MS: Rt = 0.37 min, ES<+>131 (AA standard).

Step b: (laSJbR. 5aS. 6aS)- 3-( 4-Methoxvphenyl)hexahydrooxireno[ 4. 5] svclopenta[ 1 , 2- <f|-[ 1 , 31 ] dioxin

[0178] (1R,2R,3S,5S)-3-(Hydroxymethyl)-6-oxabicyclo[3.1.0]hexan-2-ol (3.65 g, 21.0 mol) was dissolved in DCM (121 mL ) and the solution was cooled to 0 °C. 1-

(Dimethoxymethyl)-4-methoxybenzene (10.7 mL, 63.1 mmol) was added followed by pyridinium monotoluenesulfonate (530 mg, 2.11 mmol). The mixture was stirred

room temperature overnight. TLC showed complete conversion. The reaction mixture was concentrated in vacuo and the residue was purified via silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes to give the title compound (4.10 g, 78%). LC/MS: Rt = 1.68 min, ES<+>249 (AA standard).

Step c: A^-[( lS)- 2. 3- Dihydro- lil/- inden- l- vll- 7//- pvrrolo[ 2. 3- t/ 1pvrimidin- 4- amine

[0179] 4-Chloro-l/-pyrrolo[2,3-<|pyrimidine (2.10 g, 13.6 mmol) was dissolved in 1-butanol (60.0 mL) and N-diisopropylethylamine (3, 57 mL, 20.5 mmol) was added followed by (S)-(+)-1-aminoindane (1.93 mL, 15.0 mmol). The mixture was heated to reflux for 60 hours, cooled to room temperature and the solvent was evaporated to dryness. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in DCM to give the title compound (2.72 g, 80%). LC /MS: Rt =1.42 min, ES+ 251 (AA standard).

Step d: r4aS. 6R. 7S. 7aR)- 6-[ 4- r( 1S)- 2. 3- Dihvdro- li/- inden- 1- vlamino]- 7//pyrrolo[ 2, 3-^/ 1- pvrimidin- 7- yl]- 2 -( 4-methoxyphenyl)hexahydrocyclopenta[( i ][ 1. 3] dioxin- 7-ol

[0180] N-[(1S)-2,3-Dihydro-1H/-inden-1-yl]-7H/-pyrrolo[2,3-<|pyrimidin-4-amine (3.70 g, 14, 8 mmol) was dissolved in DMF (49.4 mL) under a nitrogen atmosphere. Sodium hydride (546 mg, 13.6 mmol) was added and the suspension was stirred at 70 °C for 10 min to give a clear solution. (laS,lbR,5aS,6aS)-3-(4-Methoxyphenyl)hexahydroxyreno[4,5]cyclopenta[l,2-(f|[l,3]dioxin (2.82 g, 11.4 mmol) dissolved in DMF (35.3 mL) was added the above solution and the reaction was stirred at 110 °C for 2 h.The reaction mixture was cooled, quenched with saturated aqueous sodium chloride solution (30 mL), extracted with EtOAc (3 x 50 mL), dried with MgSO 4 , filtered and evaporated under high vacuum. The residue was purified via silica gel chromatography eluting with a gradient of 30 to 100% EtOAc in hexanes to give the title compound (3.90 g, 69%). LC/MS: Rt = 1.86 min, ES<+>500. (AA standard).

Stage e: 0- IY4aS. 6R. 7S. 7aRV6- r4- r( T S)- 2. 3- Dihydro- li/- inden- l- ylamino1- 7//pvrrolo-[ 2, 3-( i] pvrimidin- 7- vl]- 2-( 4-methoxysvphenyl ) hexahdvrosvklopenta[^ 11. 31dioxin- 7- vll O-phenylthiocarbonate

[0181] (4αS,6R,7S,7αR)-6-[4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo-[2,3-( f|pyrimidin-7-yl]-2-(4-methoxyphenyl)hexahydrocyclopenta[rf]l,3]dioxin-7-ol (4.00 g, 8.02 mmol) was dissolved in DCM (169 mL) under an argon atmosphere , and 4-(dimethylamino)pyridine (2.94 g, 24.1 mmol) was added followed by phenylchlorothionocarbonate (2.22 mL, 16.0 mmol). The mixture was stirred at room temperature for 1 h. The solvent was concentrated in vacuo and purified via silica gel chromatography eluting with a gradient of 20 to 100% EtOAc in hexanes on a column pretreated with 1% TEA in hexanes to give the title compound (5.00 g, 99%). LC/MS: Rt = 2, 34 min, ES<+>636 (AA standard).

Step f: N- r( 1S)- 2. 3- Dihdro- li/- inden- 1- vl1- 7- r( 4aS. 6R. 7aS)- 2-( 4- methoxyphenyl)

hexahydrocyclopenta[ d][ 1. 3] dioxin- 6- vl]- 7//- pyrrolo[ 2. 3-( i] pvrimidin- 4-amine

[0182] O-[(4aS,6R,7S,7aR)-6-[4-[(1S)-2,3-Dihydro-1 H -inden-1-ylamino]-7 H -pyrrolo-[ 2,3-^]pyrimidin-7-yl}-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-yl] O -phenylthiocarbonate (5.00 g, 7.88 mmol) was dissolved in toluene (150 mL) under a nitrogen atmosphere, and tri- r -butyltin hydride (4.24 mL, 15.8 mmol) was added followed by 2,2'-azo-bis-isobutyronitrile (259 mg, 1.58 mmol). The solution was heated to reflux for 30 min, the mixture was cooled, the solvent was concentrated to 30 mL and the residue was purified via silica gel chromatography eluting with a gradient of 30 to 100% EtOAc in hexanes to give the title compound (3.00 g, 79 %). LC/MS: Rt = 2.12 min, ES<+>483 (AA standard).

Step: ( lS. 2S. 4R)- 4-( 4- r( lS)- 23- Dihvdro- li/- inden- l- vlamino1- 7//- pvrrolor2. 3-<f1- pvrimidin- 7- vl] - 2-(hydroxymethyl)cyclopentanol

[0183] 7N-[(1S)-2,3-Dihydro-II H-inden-1-yl]-7-[(4aS,6R,7aS)-2-(4-Methoxyphenyl)-hexahydrocyclopenta[^[l ,3]Dioxin-6-yl]-7H-pyrrolo[2,3-(f|pyrimidin-4-amine (3.00 g, 5.90 mmol) was dissolved in THE (11.6 mL), water (11.6 mL) and AcOH (34.9 mL, 614 mmol) were added. The mixture was stirred at room temperature under an argon atmosphere for 60 h. The mixture was concentrated under reduced pressure and the residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to give the title compound (2.10 g, 98%) LC/MS: Rt =1.46 min, ES<+>365 (AA standard).

Step h: ( 1S. 2S. 4RV2-( { retrr- Butvl( dimethylsilvl1oxv) methyl)- ( 4-[( 1SV2. 3-dihydro- 1//- inden- 1 - vlamino)- 7i/- pvrrolo[2,3-^]pyrimidin-7-yl]cyclopentyl acetate

[0184] (1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-(f |-pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol (3.00 g, 8.23 mmol), 1/-imidazole (1.68 g, _24.7 mmol) and 4-(dimethylamino)- pyridine (100 mg, 0.818 mmol) was dissolved in DMF (90.0 mL) under an argon atmosphere, and the solution was cooled to 0 ° C. tert -Butyldimethylsilyl chloride (1.24 g, 8.23 mmol) was added and the mixture was stirred at room temperature for 2 h. LC/MS showed complete conversion. The reaction was quenched with saturated aqueous sodium chloride solution (30 mL), extracted with EtOAc (3 x 50 mL), dried with MgSO/t, filtered and concentrated in vacuo. The remaining DMF was removed under high vacuum.Crude (1S,2S,4R)-2-({[ter;-butyl(dimethyl)silyl]oxy)methyl)-4-[4-[(1S)-2,3-dihydro- 1H-inden-1-ylamino]-7H-pyrrolo[2,3-(f|pyrimidin-7-ylcyclopentanol (3.94 g, 8.23 mmol) and 4-(dimethylamino)-pyridine (100 mg, 0.818 mol) was dissolved in pyridine (70.0 mL) and acid anhydride (4.66 mL, 49.4 mmol) was added. e stirred at room temperature overnight. The solvent was evaporated and the remaining pyridine was removed under high vacuum. The residue was purified via silica gel chromatography eluting with a gradient of 10 to 66% EtOAc in hexanes to give the title compound (3.66 g, 86%). LC/MS: Rt = 2.51 min, ES<+>521 (AA standard).

Step i: ( lS. 2S. 4R)- 4- r4- rriS)- 2. 3- Dihvdro- l//- inden- l- vlaminol- 7//- pvrrolor2. 3-</ 1- pyrimidine- 7- vIII- 2-( hydroxymethyl) cyclopentyl acetate

[0185] (1S,2S,4R)-2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4-{4-[(1S)-2,3-hydro-li/ -inden-1-ylamino]-7 H -pyrrolo[2,3-(i]pyrimidin-7-yl)cyclopentyl acetate (3.66 g, 7.03 mmol) was dissolved in THF (31.3 mL) and pyridine (31.3 mL, 387 mmol) in a polypropylene vial and the solution was cooled to 0 °C. Pyridine hydrofluoride (8.61 mL, 95.6 mmol) was added dropwise and the mixture was stirred at room temperature for 1 hour. The resulting solution was added dropwise to a solution of saturated aqueous sodium bicarbonate (150 mL), extracted with EtOAc (3 x 50 mL), dried with MgSO/t, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to give the title compound (2.30 g, 80%). LC/MS: Rt =1.64 min, ES<+>407 (AA standard).

Step i: ( 1S. 2S. 4R)- 2- ir( Aminosulfonoxyvlmetvl1- 4[ 4- r( 1S)- 2. 3- dihydro- 1//-inden- 1- vlamino]- 7//- pvrrolo[ 2 3-[1]pyrimidin-7-yl]cyclopentyl acetate

[0186] A 2.00 M solution of chlorosulfonamide in AcCN was prepared as follows: FA (2.30 mL, 61.0 mmol) was added dropwise with stirring to two chlorosulfonyl isocyanate (5.20 mL, 59.7 mmol) under nitrogen at 0 °C. after the addition was complete and the mixture had hardened, AcCN (22.5 mL) was added. The resulting solution was allowed to stand under a vented source of nitrogen overnight at room temperature.

[0187] (1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-Lf-inden-1-ylamino]-7H-pyrrolo[2,3-tf|- Pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentyl acetate (2.30 g, 5.38 mol) was dissolved in AcCN (108 mL), and TEA (3.75 mL, 26.9 mmol) was added. The solution was cooled to 0 °C and a 2.00 M solution of chlorosulfonamide in AcCN (5.38 mL, 10.8 mmol, as prepared above) was added. The mixture was stirred at room temperature for 45 minutes. TLC showed 50% conversion. Additional 2.00 M chlorosulfonamide in AcCN solution (5.38 mL, 10.8 mmol) was added and the mixture was stirred at room temperature for 15 min. At this point, TLC showed complete conversion. The mixture was quenched with MeOH (3.00 mL) and the solvent was removed in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in EtOAc to give the title compound (2.45 g, 94%). LC/MS: Rt = 1.68 min, ES<+>486 (AA standard).

Step k: (( IS 2S 4R)- 4- r4- r( lS)- 2. 3- Dihvdro- li/- indene- l- vlamino1- 7i/- pyrrolor2. 3-tf1 pvrimidine- 7- vll- 2- Hydroxycyclopentyl) methylsulfamate (compound 1-35)

[0188] (1S,2S,4R)-2-{[(Aminosulfonyl)oxy]methyl}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]- 7//-pyrrolo[2,3-rf]pyrimidin-7-yl)cyclopentyl acetate (2.45 g, 4.54 mmol) was dissolved in a 7.00 M solution of ammonia in MeOH (108 mL) and the mixture was stirred at room temperature for 5 days. Solvent was removed in vacuo, redissolved in DCM and the filtered residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to give the title compound (1.80 g, 90%).<!> H NMR (CD 3 OD, 400 MHz, 5): 8.16 (s, 1H), 7.26-7.12 (m, 5H), 6.63 (d, J= 3.6 Hz, 1H), 5 .85 (dd, J= 7.6, 7.6 Hz, 1H), 5.46-5.40 (m, 1H), 4.50-4.47 (m, 1H), 4.37 (d , J= 7.6, 9.6 Hz, 1H), 4.19 (dd, J= 7.4, 9.6 Hz, 1H), 3.08-3.02 (m, 1H), 2, 96-2.87 (m, 1H), 2.85-2.75 (m, 1H), 2.67-2.59 (m, 1H), 2.37-2.20 (m, 3H), 2.07-1.97 (m, 2H) ppm. LC/MS: Rt = 1.54 min, ES<+>444 (AA standard).

Step 1: (( IS 2S 4R)- 4-[ 4-[( lS)- 2. 3- Dihvdro- li/- inden- l- vlamino1- 7//- pvrrolo[ 2. 3-tf1 pvrimidin- 7- v]- 2- Hydroxycyclopentyl) methylsulfamate. potassium salt

[0189] ((IS 2S 4R )-4-[4-[(1S)-2,3-Dihydro-L H -inden-1-ylamino]-7 H -pyrrolo[2,3-β-pyrimidine-7- yl}-2-hydroxycyclopentyl)methylsulfamate (2.64 g, 5.66 mmol) was dissolved in MeOH (43.0 mL) and a 1002 M solution of potassium hydroxide in water (5.64 mL,

5.65 mmol) was added at room temperature and the mixture was stirred for 1 hour. The solvent was removed in vacuo and the solid residue was dried under high vacuum to

give the title compound (2.87 g, 100%).<!>H NMR (CD 3 OD, 300 MHz, 5): 8.16 (s, 1H), 7.26-7.12 (m, 5H), 6, 62 (d, J= 3.9 Hz, 1H), 5.85 (dd, J= 7.8, 7.8 Hz, 1H), 5.50-5.40 (m, 1H), 4.51 -4.48 (m, 1H), 4.22 (dd, J= 8.6, 10.0 Hz, 1H, 4.05 (dd, J= 6.6, 10.0 Hz, 1H), 3 .10-3.00 (m, 1H), 2.96-2.85 (m, 1H), 2.81-2.71 (m, 1H), 2.68-2.58 (m, 1H) , 2.37-2.13 (m, 3H), 2.07-1.94 (m, 2H) ppm LC/MS: Rt =1.54 min, ES<+>444 (AA standard).

Example 2 ((1S,2S,4R)-4-{4-[(1R)-2,3-Dihydro-1#-indene 1-ylamino]-7/-

pyrrolo[2,3-(i]-pyrimidin-7-yl]-2-hydroxycyclopentyl)methylsulfamate

(connection 1-13)

Step a: 4-(Benzylsulfanyl)-7//-pyrrolo[ 2.3-(/1pyrimidine)

[0190] To a round bottom flask was added 4-chloro-Lf/-pyrrolo-[2,3-^]pyrimidine (5.07 g, 33.0 mmol), in addition to 1.00 M of KO-r -Bu in THF (49.5 mL, 49.5 mmol) and benzenemethanethiol (5.81 mL, 49.5 mmol) in isopropyl alcohol (350 mL). The reaction mixture was heated to reflux at 85 °C under a nitrogen atmosphere. After 48 hours, the reaction mixture was cooled and solvent removed in vacuo. To the residual concentration was added water (300 mL) and the solution was filtered to collect the resulting white solid. The solid was washed with diethyl ether and MeOH and dried under vacuum to give the product as a white solid (6.29 g, 79% yield). LC/MS: Rt = 1.68 min, ES<+>242 (FA standard). Reference: Pathak, A. K., Pathak, V., Seitz, L. E., Suling, W. J., Reynolds, R. C. J. Med. Chem., 2004, 47, 273-276.

Step b: ( 4aS. 6R. 7SJaR)- 6-[ 4-( Benzvlsulfanvl)- 7//- pyrrolo[ 23-^ 1Privrimidine- 7-vl]- 2-( 4- methoxysvphenyl) hexahydrosvclopenta[^ 1[ 1. 3] dioxin-7-ol

[0191] A round bottom flask under argon was charged with 4-(benzylsulfanyl)-7//-pyrrolo[2,3-^]pyrimidine (194 mg, 0.804 mmol) and DMF (5.00 mL) followed by a 1.00 M solution of lithium hexamethyldisilazide in THF (0.603 mL, 0.603 mmol). The reaction mixture was heated to 60 °C. After 10 min, (laS,lbR,5aS,6aS)-3-(4-methoxyphenyl)hexahydroxyreno[4,5]cyclopenta[l,2- <i][1,3]dioxin (100 mg, 0.403 mmol, as prepared in example la-b) in DMF (2.00 mL) was added and the reaction was heated to 110 °C. After 6 hours, the reaction mixture was cooled to room temperature and a saturated aqueous sodium chloride solution (50.0 mL) was added. The aqueous layer was washed with EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 100 mL), dried over MgSO/t, filtered and concentrated in vacuo. Purification via silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexanes afforded the title compound as a white solid (197 mg, 93%). LC/MS: Rt = 2.07 min, ES<+>490. (FA standard).

Step: 0- r( 4aS. 6R. 7S. 7aR)- 6-[ 4-( Benzvlsulfanvl)- 77f- pvrrolo[ 2. 3- 6nprimidin- 7-vl]- 2-( 4- methoxyphenyl)hexahydrocyclopenta[(/ 1[ 1. 3] dioxin- 7- vl] O - phenylthiocarbonate

[0192] A solution of (4aS,6R,7S,7aR)-6-[4-(benzylsulfanyl)-7/- pyrrolo[2,3-d]-pyrimidin-7-yl]-2-(4- methoxyphenyl)hexahydrocyclopenta[<f] [1,3] dioxin-7-ol (990 mg, 2.02 mmol) in DCM (57.0 mL) was added 4-(dimethylamino)-pyridine (748 mg, 6.07 mmol) and phenylchlorothionocarbonate (0.565 mL, 4.04 mol) under a nitrogen atmosphere, and the yellow reaction was stirred at room temperature. After 12 h, the dark yellow solution was purified via silica gel chromatography eluting with 10% EtOAc in hexanes and then 10% MeOH in DCM on a column pretreated with with 1% TEA in hexanes to give the title compound as a yellow oil (1.77 g, 97%). LC/MS: Rt = 2.47 min, ES<+>626 (FA standard).

Step d: 4- rBenzylsulfanyl)- 7-[( 4aS . 6R . 7aS )- 2-( 4-Methoxphenyl)hexahydrocyclopenta[^] - [ 1. 3] dioxin- 6- yl]- 7H - pvrrolo[ 2. 3 -^ pvrimidine

[0193] A solution of 0-[(4aS,6R,7S,7aR)-6-[4-(benzylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-(4- Methoxyphenyl)hexahydrocyclopenta[<f] [1,3]dioxin-7-yl]Ophenyltocarbonate (1.77 g, 1.98 mmol) in toluene (91.0 mL) was added 2,2'-azo-bisisobutyronitrile (67 .7 mg, 0.404 mmol) and tri-r-butyltin hydride (1.11 mL, 4.00 mmol) under a nitrogen atmosphere. The yellow solution was heated to reflux at 140 °C. After 2 h, the reaction mixture was cooled, silica gel was added, and the solvent was removed in vacuo. Silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexanes afforded the title compound as a partial solid (800 mg, 85%). LC/MS: Rt = 2.38 min, ES<+>475 (FA standard).

Step e: 4-( Benzylsulfonvl)- 7- r( 4aS. 6R. 7aS)- 2-( 4-methoxypheny 1 ) hexahydrocyclopenta[^ l [ 1. 3] dioxin- 6- vl] - 7//- pvrrolo [ 2. 3 - ^ pvrimidine

[0194] To a round bottom flask with a stir bar was added 4-(benzylsulfanyl)-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[<i][l,3]dioxin-6 -yl]-7 H -pyrrolo[2,3-fr]pyrimidine (693 mg, 1.32 mmol) and DCM (32.5 mL). Sodium bicarbonate (400 mg, 4.76 mmol) was added followed by 3-chloroperbenzoic acid (754 mg, 3.36 mol) and the reaction mixture was stirred for 12 h. The reaction mixture was then treated with saturated aqueous sodium bicarbonate solution, extracted with DCM and the combined organic layers were dried over MgSO/t, filtered and concentrated in vacuo. Silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexanes gave the product as a white solid (219 mg, 32%). LC/MS: Rt = 1.94 min, ES<+>506 (FA standard).

Step f: 7V- r( 1R)- 2. 3- Dihdro- i//- inden- 1- vl1- 7-[( 4aS. 6R. 7aS)- 2-( 4- methoxysphenvl)

hexahydrocyclopenta[ 6ri[ 1, 3] dioxin- 6- vl]- 7//- pvrrolo[ 2, 3-^] pvrimidin- 4-amine

[0195] In a 0.5-2 mL microwave vial, 4-(benzylsulfonyl)-7-[(4aS,6R,7aS)-2-(4-hexahydrocyclopenta[<f][1,3]dioxin-6-yl ]-7ii/-pyrrolo[2,3-(f|pyrimidine (100 mg, 0.198 mmol), (R)-(~)-l-aminoindane (0.127 mL, 0.989 mmol) and DIPEA (0.172 mL, 0.989 mol) dissolved in ethanol (1.22 mL). The vial was sealed and heated to 110 °C overnight. The solution was then concentrated in vacuo and the resulting material was purified via silica gel chromatography eluting with a gradient of 20 to 50% EtOAc in hexanes which gave an orange colored oil as product (70.0 mg, 73%) LC/MS: Rt = 1.42 min, ES<+>483 (FA standard).

Step: ( lS. 2S. 4R)- 4- r4- r( lR)- 2. 3- Dihvdro- l//- inden- l- vlamino1- 7//- pvrrolor2. 3-[f1pyrimidine-7-v]-2-(hydroxymethyl)sylclopentanol

[0196] 7N-[(1R)-2,3-Dihydro-4H-inden-1-yl]-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[(f |[1,3]dioxin-6-yl]-7//-pyrrolo[2,3-(i]pyrimidin-4-amine (70.0 mg, 0.145 mmol) was added to a solution of AcOH (0.742 mL , 13.0 mmol), THF (0.235 mL) and water (0.261 mL). The solution was stirred at room temperature for 4 days before being concentrated in vacuo. Silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM gave the title compound (27.6 mg, 52%) LC/MS: Rt = 0.94 min, ES<+>365 (FA standard).

Step h: terf-Butyl (chlorosulfonyl) carbamate

[0197] To a stirred solution of chlorosulfonyl isocyanate (3.20 mL, 36.0 mmol) in benzene (15.0 mL) in a water bath was added tert-butyl alcohol (3.50 mL, 36.2 mmol) dropwise via a syringe under nitrogen atmosphere. After 2 h, the mixture was dissolved in hexanes (30.0 mL) and the resulting white precipitate was filtered and washed with hexanes (3 x 20 mL). The collected e-matter was dried in a vacuum drier under house vacuum for 10 min to give the title compound as a white solid (5.08 g, 65%). The product was stored under nitrogen in a freezer. <!>H NMR (300 MHz, CDCb, 5): 8.44 (br s, 1H), 1.57 (s, 9H) ppm. LC/MS: Rt = 0.939 min, ES<+>215 (AA standard). Reference: F. Hirayama et al, Bioorg. With. Chem., 2002, 10, 1509-1523.

Step i: fert- Butyl { rrriS. 2S. 4R)- 4- r4- rriR)- 2. 3- Dihydro- li/- inden- 1- ylamino1-7//- pyrrolo[ 2. 3-( i] pyrimidine- 7- vl]- 2-hydroxyvsvclopentvDmethoxyvsvlsulfonvljcarbamate

[0198] (1S,2S,4R)-4-[4-[(1R)-2,3-Dihydro-Lf-inden-1-ylamino]-7iH-pyrrolo[2,3-tf|pyrimidine- 7-yl)-2-(hydroxymethyl)cyclopentanol (27.6 mg, 0.117 mmol) and 2,6-di-tert-butyl-4-methylpyridine (48.5 mg, 0.236 mmol) were suspended in AcCN (1, 57 mL) and cooled to 0 °C. tert-Butyl (chlorosulfonyl)carbamate was added and the mixture was warmed to room temperature overnight. The reaction was quenched via addition of MeOH (1.00 mL) and concentrated in vacuo. Silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM afforded the title compound (15.2 mg, 37%). LC/MS: Rt = 1.29 min, ES<+>544 (FA standard).

Step i: (( 1 S . 2 S . 4 R )- 4-( 4- IY1 R )- 2 . 3- dihydro- lif-inden- 1 - ylamino1- 7if-pyrrolo[ 2, 3-(/ 1- pvrimidin- 7- vll- 2- hvdroksvsvclopentvl) metvlsulfamate

(connection 1-13)

[0199] tert-Butyl {[((1S,2S,4R)-4-{4-[(1R)-2,3-dihydro-1 H -inden-1-ylamino]-7 H -pyrrolo[ 2,3-t/]pyrimidin-7-yl}-2-hydroxycyclopentyl)methoxy]sulfonyl)carbamate (31.0 mg, 0.0570 mmol) was dissolved in DCM (0.803 mL), and trifluoroacetic acid (0.803 mL, 10.4 mmol) was added. The solution was stirred at room temperature for 15 minutes before being concentrated in vacuo. The residue was taken up in MeOH (5.00 mL), treated with solid sodium bicarbonate (300 mg) and stirred for 10 minutes. Filtration and silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM gave the title compound (7.20 mg, 58%), !H NMR (400 MHz, CD3OD, 5): 8.17 (s, 1H ), 7.27-7.14 (m, 5H), 6.64 (d, J= 3.5 Hz, 1H), 5.86 (t, J= 7.5 Hz, 1H), 5.49 -5.42 (m, 1H), 4.51-4.48 (m, 1H), 4.38 (dd, J= 7.5, 9.8 Hz, 1H), 4.21 (dd, J = 7.3, 9.8 Hz, 1H), 3.10-3.03 (m, 1H), 2.97-2.88 (m, IH, 2.86-2.76 (m, 1H) , 2.68-2.60 (m, 1H), 2.37-2.21 (m, 3H), 2.08-1.97 (m, 2H) ppm, LC/MS: Rt = 1.16 min, ES<+>444 (FA standard).

Example 3: [(1S,2R,3S,4R)-2,3-Dihydroxy-4-[4-(phenylsulfanyl)-7/-pyrrolo[2,3-^]-pyrimidin-7-yl]cyclopentyl] methylsulfamate (compound 1-53)

Step a: 4-(Phenylsulfanyl)-7//-pvrrolo[2.3-^]pvrimidine

[0200] A solution of 4-chloro-l/-pyrrolo[2,3-<f]pyrimidine (1.69 g, 11.0 mmol) and TEA (4.60 mL, 33.0 mmol) in 1- butanol (25.0 mL) was added to benzenethiol (3.39 mL, 33.0 mmol) and the mixture was refluxed at 140 °C overnight. The reaction was then cooled to room temperature and concentrated in vacuo. The off-white solid was purified by silica gel chromatography eluting with a gradient of 0 to 35% EtOAc in DCM to give the product (2.29 g, 92%). LC/MS: Rt = 1.55 min, ES<+>228 (FA standard).

Step b: ( 4aS . 6R . 7S . 7aR )- 2-( 4- Methoxyphenyl)- 6- r 4-( phenylsulfan- li/- t3vrrolor3. 2-c ] - pyridine- 1 - ylylhexahydrocyclopentar^/ l | T , 31 dioxin - 7- etc

[0201 ] A mixture of 4-(phenylsulfanyl)-7//-pyrrolo[2,3-fr]pyrimidine (895 mg, 3.94 mmol) and NaH (148 mg, 3.69 mmol) in dry DMF (12 .0 mL) was stirred at 60 °C for 10 minutes. Then (laS,lbR,5aS,6aS)-3-(4-methoxyphenyl)hexahydroxyreno[4,5]cyclopenta[l,2-(i][l,3]-dioxin (611 mg, 2.46 mmol) was added and the mixture was heated to 110 °C for 5 h. The reaction mixture was then cooled to room temperature, quenched with a saturated aqueous sodium chloride solution, and the solution was extracted twice with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated in in vacuo. The crude product mixture was purified by silica gel chromatography eluting with a gradient of 5 to 30% EtOAc in DCM to afford the title compound (96.5 mg, 8.24%). LC/MS: Rt =1.95 min, ES<+>476 (FA standard).

Step: ( 1S . 2R . 3S . 5R )- 3-( Hydroxymethyl)- 5- r 4-( phenylsulfan- 7i/- pvrrolo[ 2. 3-^- pyrimidin- 7- yl] sylclopentane- 1, 2- diol

[0202] A solution of AcOH (1.04 mL, 18.3 mmol), THF (0.330 mL) and water (0.366 mL) was added to (4aS,6R,7S,7aR)-2-(4-methoxyphenyl)-6 -[4-(phenylsulfanyl)-li/-pyrrolo[3,2-c]pyridin-1-yl]hexahydrocyclopenta[^][1,3]dioxin-7-ol (96.7 mg, 0.203 mmol). The reaction solution was stirred at room temperature for 48 hours and then concentrated in vacuo. The resulting oil was purified by silica gel chromatography eluting with a gradient of 60 to 100% EtOAc in hexanes to give the title compound (32.0 mg, 44%). LC/MS: Rt = 1.33 min, ES<+>358 (FA standard).

Step d: r( 3aR. 4S. 6R. 6aS)- 2. 2- Dimetvl- 6- r4-(^

^ pvrimidin- 7- vlltetrahydro- 3ai/- svclopenta[(/ 1[ 1. 31dioxol- 4- vllmethanol

[0203] (1S,2R,3S,5R)-3-(Hydroxymethyl)-5-[4-(phenylsulfanyl)-7 H -pyrrolo[2,3-d]-pyrimidin-7-yl]cyclopentan-1 ,2-diol (320 mg, 0.0895 mmol), 2,2-dimethoxypropane (0.0549 mL, 0.446 mmol) and p-toluenesulfonic acid monohydrate (17.0 mg, 0.0895 mmol) were dissolved in acetone (2, 20 mL) and stirred at room temperature overnight. The reaction was then cooled with a saturated sodium bicarbonate solution and approx. half of the solvent was removed in vacuo. The resulting residue was diluted with water and extracted with DCM (3x). Combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a white foam (35.5 mg, 99%) which was used without further purification. LC/MS: Rt =1.72 min, ES<+>389 (FA standard).

Step: [( 3aR. 4R. 6R. 6aSV2. 2- Dimethyl- 6- r4-( phenylsulfanyl)- 7//- pvrrolo[ 2. 3-tf1 pvrimidin- 7- vl] tetrahydro- 3ai/- svclopenta[^ 1 [ 1. 3] dioxol-4-yl] methylsulfamate

[0204] A solution of [(3aR,4S,6R,6aS)-2,2-dimethyl-6-[4-(phenylsulfanyl)-7i/-pyiTolo[2,3-^pyrimidin-7-yl]tetrahydro- 3αi/-cyclopenta[rf][1,3]dioxol-4-yl}methanol (35.5 mg, 0.0893 mmol) and pyridine (0.0325 mL, 0.402 mmol) in dry DCM (1.00 mL) was cooled in an ice bath. To this solution was added a 2.00 M chlorosulfonamide solution in AcCN (0.178 mL, 0.356 mmol as prepared in Example 1j), and the reaction was warmed to room temperature and stirred for 4 hours. The mixture was diluted with DCM, washed with water and extracted with DCM (3x). Combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by silica gel chromatography eluting with a gradient of 50 to 70% EtOAc in hexanes to give the title compound as a white solid (14.4 mg, 34%). LC/MS: Rt = 1.81 min, ES<+>477 (FA standard).

Step f: r( 1R. 2R. 3S. 4R)- 2. 3- dihvdroksv- 4- r4- rfenvlsulfanvn- 7//- pvrrolor2. 3-^1-pyrimidine-7-cyclopentylmethylsulfamate (compound 1-53)

[0205] {(3aR,4R,6R,6aS)-2,2-Dimethyl-6-[4-(phenylsulfanyl)-7/-pyrrolo[2,3-rf]-pyrimidin-7-yl]tetrahydro- 3aif-Cyclopenta[(i][1,3]dioxol-4-yl}methylsulfamate (14.4 mg, 30.2 mmol) was stirred in 1.00 mL of 90% trifluoroacetic acid in water for 3 h at room temperature. was then removed in vacuo and the resulting oil was purified by silica gel chromatography eluting with a gradient of 60 to 100% EtOAc in hexanes to give the title compound (7.50 mg, 57%).<!>H NMR (400 MHz , CD3OD, 5): 8.45 (s, 1H), 7.66-7.36 (m, 2H), 7.51-7.41 (m, 4H), 5.92 (d, J= 3 .8 Hz, 1H), 5.13-5.06 (m, 1H), 4.58-4.55 (dd, J= 3.8, 9.0 Hz, 1H), 4.42-4, 37 (dd, J= 8.0, 9.8 Hz, 1H), 4.18-4.14 (m, 2H), 2.92-2.82 (m, 1H), 2.24-2, 08 (m, 2H) ppm LC/MS: Rt = 1.38 min, ES<+>437 (FA standard).

Example 4: [(1S,2S,4R)-2-Hydroxy-4-(4-{[(1R)-1-phenylethyl]amino}-7/-pyrrolo[2,3-<f]pyrimidine-7 -yl)cyclopentyl]methylsulfamate (compound 1-7)

[0206] The title compound was prepared by following the procedure described in Example la-k, and R-(+)-α-methylbenzylamine was used in step c.<*>H NMR (400 MHz, CD 3 OD, 5): 8, 05 (s, 1H), 7.41-7.38 (m, 2H), 7.31-7.26 (m, 2H), 7.21-7.16 (m, 2H), 6.71 ( d, J= 3.5 Hz, 1H), 5.46-5.38 (m, 2H), 4.50-4.46 (m, 1H), 4.38-4.34 (dd, J= 7.5, 9.8 Hz, 1H), 4.21-4.17 (dd, J= 7.3, 9.8 Hz, 1H), 2.84-2.74 (m, 1H), 2 .35-2.15 (m, 3H), 2.06-1.98 (m, 1H), 1.59 (d, J = 6.8 Hz, 3H) ppm. LC/MS: Rt = 1.16 min, ES<+>432 (FA standard).

Example 5: [(1S,2S,4R)-2-Hydroxy-4-(4-{methyl[(1S)-1-phenylethyl]amino)-7i/-

pyrrolo-[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate (compound 1-3)

[0207] The title compound was prepared following the procedure described in Example 1a-k, and (S)-(-)-A^,a-dimethylbenzylamine was used in step c.<!>H NMR (CD 3 OD, 300 MHz, 5): 8.16 (s, 1H), 7.34-7.20 (m, 6H), 6.64 (d, J= 3.6 Hz, 1H), 6.41-6.34 (m , 1H), 5.54-5.43 (m, 1H), 4.51-4.48 (m, 1H), 4.24 (dd, J= 9.6, 9.6 Hz, 1H), 4.07 (dd, J = 6.9, 9.6 Hz, 1H), 3.03 (s, 3H), 2.80 2.70 (m, 1H), 2.37-2.14 (m , 3H), 2.02-1.88 (m, 1H), 1.64 ( d, J = 7.2 Hz, 3H) ppm. LC/MS: Rt = 1.64 min, ES<+>446 (AA standard).

Example 6: ((1S,2S,4R)-4-(4-[(4S)-3,4-Dihydro-2//-chromen-4-ylamino]-7//-

pyrrolo[2,3-(i]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate

(connection 1-12)

[0208] The title compound was prepared following the procedure described in Example 1a-k, and (4S)-chroman-4-amine was used in step c.<!>H NMR (CD 3 OD, 400 MHz, 5): 8, 28 (s, 1H), 7.43 (d, J= 3.6 Hz, 1H), 7.27-7.20 (m, 2H), 6.94-6.85 (m, 3H), 5 .56-5.48 (m, 1H), 5.34-5.30 (m, 1H), 4.54-4.49 (m, 1H), 4.38 (dd, .7= 7.4 , 9.8 Hz, 1H), 4.33-4.29 (m, 2H), 4.21 (dd, J= 7.6, 9.8 Hz, 1H), 2.90-2.80 ( m, 1H), 2.39-2.05 (m, 6H) ppm. LC/MS: Rt = 1.51 min, ES<+>460 (AA standard).

Example 7: ((1S,2S,4R)-4-{4-[(2,6-Difluorobenzyl)amino]-7 H -pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl )methylsulfamate (compound 1-15)

[0209] The title compound was prepared following the procedure described in Example 1a-k, and (2,6-difluorophenyl)methanamine was used in step c. <!>H NMR (CD 3 OD, 300 MHz, 5): 8.17 (s, 1H), 7.39-7.29 (m, 1H), 7.16 (d, J= 3.6 Hz, 1H), 7.00-6.94 (m, 2H), 6, 60 (d, J= 3.6 Hz, 1H), 5.48-5.37 (m, 1H), 4.80 (s, 2H), 4.50-4.46 (m, 1H), 4 .36 (dd, 7 = 7.6, 9.6 Hz, 1H), 4.19 (dd, J= 7.2, 9.6 Hz, 1H), 2.85-2.72 (m, 1H ), 2.36-2.00 (m, 4H) ppm. LC/MS: Rt = 1.42 min, ES<+>454 (AA standard).

Example 8: {(1S,2S,4R)-4-[4-(Benzylamino)-7H/-pyrrolo[2,3-^]pyrimidin-7-yl]-2-hydroxycyclopentyl}methylsulfamate (compound 1-49 )

[0210] The title compound was prepared following the procedure described in 1a-k, and benzylamine was used in step c. <!>H NMR (CD 3 OD, 400 MHz, 5): 8.12 (s, 1H), 7, 36-7.20 (m, 6H), 6.62 (d, J= 3.6 Hz, 1H), 5.49-5.40 (m, 1H), 4.76 (s, 2H), 4 .50-4.48 (m, 1H), 4.37 (dd, J= 7.6, 10.0 Hz, 1H), 4.20 (dd, J= 7.6, 10.0 Hz, 1H ), 2.85-2.76 (m, 1H), 2.36-2.19 (m, 3H), 2.08-2.00 (m, 1H) ppm. LC/MS: Rt = 1.20 min, ES<+>418 (FA standard).

Example 9: [(1S,2S,4R)-2-Hydroxy-4-(4-([(1S)-1-phenylethyl]amino]-7i)-pyrrolo[2,3-<f]-pyrimidine-7 -yl)cyclopentyl]methylsulfamate (compound 1-4)

[0211] The title compound was prepared by following the procedure described in Example 1a-k, and (lS)-(-)-α-methylbenzylamine was used in step c.<!>H NMR (400 MHz, CD 3 OD, 5): 8.05 (s, 1H), 7.41-7.39 ( d, J= 7.6 Hz, 2H), 7.31-7.27 (m, 2H), 7.22-7.17 ( m, 2H), 6.72 (d, J = 3.3 Hz, 1H), 5.46-5.38 (m, 2H), 4.48-4.47 (br s, 1H), 4, 37 (dd, J= 7.6, 9.6 Hz, 1H), 4.21-4.17 (m, 1H), 2.84-2.75 (m, 1H), 2.37-2, 18 (m, 3H), 2.07-1.94 (m, 1H), 1.61-1.59 (d, J = 7.0 Hz, 3H) ppm. LC/MS: Rt= 1.50 min, ES<+>432 (AA standard).

Example 10: ((1S,2S,4R)-4-(4-[Benzyl(methyl)amino]-7i/-pyrrolo[2,3-^]pyrimidin-7-yl)-2-hydroxycyclopentyl)methylsulfamate (compound I-10)

[0212] The title compound was prepared following the procedure described in Example 2a-j, and 7N-methylbenzylamine was used in step f.<*>H NMR (400 MHz, DMSO-d6, 5): 8.24 (s, 1H), 7.44-7.25 (m, 5H), 7.31-7.23 (m, 3H), 6.64 (br s, 1H), 5.49-5.37 (m, 1H ), 5.04 (s, 2H), 4.37-4.30 (m, 1H), 4.23 (dd, J= 7.0, 9.7 Hz, 1H), 4.04 (dd, J = 8.0, 9.6 Hz, 1H), 3.35 (s, 3H), 2.77-2.64 (m, 1H), 2.22-1.87 (m, 4H) ppm. LC/MS: Rt = 1.51 min, ES<+>432 (AA standard).

Example 11: ((1S,2S,4R)-4-(4-[(2-Chlorobenzyl)amino]-7if-pyrrolo[2,3-rf]pyrimidin-7-yl)-2-hydroxycyclopentyl)methylsulfamate (compound I-l)

[0213] The title compound was prepared following the procedure described in Example 2a-j, and 2-chlorobenzylamine was used in step f. <!>H NMR (400 MHz, DMSO-^6, 5): 8.10 (s , 1H), 8.03-7.94 (m, 1H), 7.48-7.42 (m, 1H), 7.38 (s, 1H), 7.36-7.24 (m, 4H ), 6.65 (d, J=3.2 Hz, 1H), 5.36 (dt, J= 8.9, 14.2 Hz, 1H), 4.89 (d, .7=3.9 Hz, 1H), 4.76 (d, J= 5.9 Hz, 2H), 4.36-4.30 (m, 1H), 4.24 (dd, J= 7.0, 9.7 Hz , 1H), 4.05 (dd, J= 8.1, 9.5 Hz, 1H), 2.77-2.66 (m, 1H), 2.24-2.02 (m, 3H), 1.99-1.89 (m, 1H) ppm. LC/MS: Rt = 1.51 min, ES<+>452 (AA standard).

Example 12: ((1S,2S,4R)-2-Hydroxy-4-[4-(methylamino)-7i7-pyrrolo[2,3-tf|pyrimidin-7-yl]-cyclopentyl)methylsulfamatoge ((1S,2S ,4R)-4-[4-[(1S)-2,3-dihydro-1H-inden-1-yl (methyl)amino]-77H-pyrrolo[2,3-(f|pyrimidin-7- yl)-2-hydroxycyclopentyl)methylsulfamate (compounds 1-40 and 1-6)

Step a: fe/ t-Butyl ( 1 S )- 2, 3- dihydro- 17/- inden- 1 -yl carbamate

[0214] To a solution of (S)-(+)-1-aminoindane (1.24 g, 9.22 mmol) in THF (20.0 mL) was added TEA (1.42 mL, 10.1 mmol) followed by of di-tert-butyl dicarbonate (2.07 g, 9.22 mmol) and the mixture was stirred under a nitrogen atmosphere for 24 h. The mixture was concentrated in vacuo and purified by silica gel chromatography eluting with a gradient of 0 to 20% EtOAc in hexanes to give the title compound as a white solid (2.02 g, 94%). LC /MS: Rt = 1.94 min, ES<+>234 (AA standard).

Step b: fe/ t-Butyl ( 1S)- 2. 3- dihydro- 17/- indene- 1- vl( metvl) carbamate

[0215] A solution of tert-butyl (1 S )-2,3-dihydro-1 H -inden-1 -yl carbamate (1.82 g, 7.80 mmol) in THF (50.0 mL) under argon atmosphere at 0 °C, 60% sodium hydride in mineral oil (968 mg, 24.2 mmol) was added and the suspension was warmed to room temperature and stirred for 30 min. Iodomethane (1.52 mL, 24.2 mmol) was added and the mixture was stirred overnight. The reaction was then quenched by the addition of a saturated ammonium chloride solution (10.0 mL) and concentrated in vacuo. The mixture was then partitioned between water (20 mL) and DCM (50 mL) and the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo and purified by silica gel chromatography eluting with a gradient of 0 to 20% EtOAc in hexanes to give the title compound as a clear, colorless oil (1.84 g, 95% ). LC/MS: Rt = 2.21 min, ES<+>248 (AA standard).

Step c: ( 1 S )- iV- Metvlindan- 1 - amine, hydrochloride salt

[0216] A solution of tert-butyl (1S)-2,3-dihydro-1H-inden-1-yl(methyl)carbamate (1.84 g, 7.44 mmol) in MeOH (50.0 mL) under a nitrogen atmosphere, hydrochloric acid (6.00 mL, 72.4 mmol) was added and the mixture was stirred overnight. The reaction was concentrated in vacuo to give the title compound as a white solid without further purification (1.35 g, 99%). LC/MS: Rt = 0.85 min, ES<+>148 (AA standard).

Step d fe/ t- Butyl ([(( 1S, 2S, 4R)- 4-{ 4- r( 1S)- 2 3- dihydro- 1//- indene- 1-vl( methyl) aminol- 7// - pvrrolo[ 2, 3-^lpvrimidin-7-yl|- 2-hydroxycyclopentyl methoxysulfony 1 ] carbamate

[0217] The title compound was prepared by following the procedure described in Example 2a-i, and (1S)-A^-methylindan-1-amine, hydrochloride salt was used in step f. LC/MS: Rt = 1.55 min, ES<+>558 (AA standard).

Step e: {( 1S. 2S. 4R)- 2-Hydroxv- 4-[ 4-( methylamino)- 7//- pyrrolo[ 2. 3- 6ripvrimidin-7- vl1- svclopentvl1metvlsulfamatog rriS. 2S. 4R)- 4-{ 4-[( lS)- 2. 3- dihvdro-l//- inden- l- vl( metvl) aminol- 7i/- pvrrolo[ 2. 3-^ 1pvrimidin- 7- yll- 2 -hydroxycyclopentyDmethylsulfamate (compounds 1-40 and 1-6)

[0218] A solution of tert-butyl {[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1#-inden-1-yl(methyl)amino]- To 7i/-pyrrolo[2,3-<f|pyrimidin-7-yl}-2-hydroxycyclopentyl)methoxy]-sulfonyl}carbamate (97.9 mg, 0.176 mmol) in DCM (5.00 mL) under nitrogen atmosphere was added trifluoroacetic acid (5.00 mL, 64.9 mmol). LC/MS after 10 min indicated the presence of both products, and the mixture was concentrated in vacuo and purified by silica gel chromatography eluting with a gradient of 0 to 10% MeOH in EtOAc to give both products as clear, colorless oils (9.70 mg, 10% and 30.6 mg, 51%, respectively). Analytical data for ((1S,2S,4R)-2-Hydroxy-4-[4-(methylamino)-7i/-pyrrolo[2,3-(i]pyrimidin-7yl]-cyclopentyl}methylsulfamate (compound 1-40 ):<!>H NMR (400 MHz, CD3OD, 5): 8.18 (s, 1H), 7.38 (d, J= 3.6 Hz, 1H), 6.74 (d, J = 3 ,1 Hz, 1H), 5.53-5.42 (m, 1H), 4.51-4.47 (m, 1H), 4.37 (dd, J= 7.5, 9.8 Hz, 1H), 4.19 (dd, 7 = 7.4, 9.7 Hz, 1H), 3.34 (s, 3H), 3.14 (br s, 3H), 2.90-2.75 ( m, 1H), 2.37-2.18 (m, 3H), 2.12-1.96 (m, 1H) ppm. LC/MS: Rt = 1.03 min, ES<+>342 (AA -standard). Analytical data for ((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1/-inden-1-yl(methyl)amino]-7/ - pyrrolo[2,3-rf]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (compound 1-6): <!>H NMR (400 MHz, CD3OD, 5): 8.28 (s, 1H) , 7.54 ( d, J= 3.8 Hz, 1H), 7.39-7.21 (m, 4H), 7.02 (d, J= 3.8 Hz, 1H), 6.26 ( dd, J= 7.5, 7.5 Hz, 1H), 5.58 (ddd, J= 5.2, 8.9, 17.9 Hz, 1H), 5.47(s, 1H), 4 .51 (dd, J=3.3, 3.3 Hz, 1H), 4.38 (dd, J= 7.4, 9.8 Hz, 1H), 4.20 (dd, J= 7.5 , 9.7 Hz, 1H), 3.23-2.96 (m, 6H), 2.93-2.79 (m, 1H), 2.76-2.59 (m, 1H), 2, 42-2.05 (m, 6H) ppm. LC/MS: Rt = 1.89 min, ES<+>458 (AA standard).

Example 13: {(1S,2S,4R)-4-[4-(Benzylamino)-5-fluoro-7H/-pyrrolo[2,3-(f|pyrimidin-7-yl]-2-hydroxycyclopentyl}methylsulfamate ( connection 1-31)

Step a: 4- Chloro- 5- lfluoro- 7i/- pyiTolo[ 2, 3-( i] pvrimidm

[0219] To a stirred solution of 4-chloro-l/-pyrrolo[2,3-^pyrimidinm (3.00 g, 19.5 mmol) in AcCN (148 mL) was added Selectfluor™ (1-chloromethyl-4-fluoro -1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)), 10.4 g, 29.4 mmol) and AcOH (29.8 mL, 524 mmol), and then the mixture was stirred for 26 h at 70 °C under nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated in vacuo, and the mixture was co-evaporated with dry toluene (2 x 30 mL). The residue was dissolved in a solution of 50% DCM in EtOAc and filtered through a pad of silica gel which was washed thoroughly. The filtrate was concentrated in vacuo, the residue was purified by silica gel chromatography eluting with a gradient of 0 to 30% EtOAc in DCM to give the title compound as a light brown solid (1.22 g, 36%). LC/MS: Rt = 1.51 min, ES<+>243 (AA standard).

Step b: (( 1 S . 2 S . 4 R )- 4- r 4-( Benzylamino)- 5- fluoro- 7//- pvrrolor2. 3- 6npvrimidin- 7-yl- 2- hydroxyvsvclopentyl) methylsulfamate (compound 1- 31)

[0220] The title compound was prepared by following the procedure described in Example la-k, and benzylamine and 4-chloro-5-fluoro-7iH-pyrrolo[2,3-d]pyrimidine were used in step c.<!> H NMR (400 MHz, CD3OD, δ): 8.09 (s, 1H), 7.37-7.32 (m, 2H), 7.31-7.26 (m, 2H), 7.23- 7.19 (m, 1H), 7.06 (d, J= 2.0 Hz, 1H), 5.50-5.42 (m, 1H), 4.76 (br s, 2H), 4, 47-4.43 (m, 1H), 4.34 (dd, J= 7.8, 9.8 Hz, 1H), 4.17 (dd, J= 7.2, 9.8 Hz, 1H) , 2.81-2.72 (m, 1H), 2.29 (ddd, J= 1.5, 8.0 Hz, 14.0 Hz, 1H), 2.25-2.13 (m, 2H ), 1.98 (ddd, J = 5.0, 9.4, 14.0 Hz, 1H). LC/MS: Rt =1.56 min, ES<+>436 (AA standard).

Example 14: ((1S,2S,4R)-4-{4-[(Cyclohexylmethyl)amino]-7/-pyrrolo[2,3-^pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (compound I -29)

[0221 ] The title compound was prepared following the procedure described in Example la-k, and cyclohexanemethylamine was used in step c.<*>H NMR (300 MHz, CD3OD, 5): 8.08 (s, 1H), 7 .17 (d, J= 3.6 Hz, 1H), 6.60 (d, J= 3.6 Hz, 1H), 5.47-5.35 (m, 1H), 4.50-4, 46 (m, 1H), 4.36 (dd, J= 7.6, 9.8 Hz, 1H), 4.19 (dd, J= 7.3, 9.8 Hz, 1H), 3.35 (br s, 1H), 3.34 (br s, 2H), 3.32 (br s, 1H), 2.85-2.72 (m, 1H), 2.36-2.15 (m, 3H), 2.01 (ddd, J= 4.9, 9.2, 14.3 Hz, 1H), 1.88-1.60 (m, 6H), 1.36-1.15 (m, 3H), 1.06-0.91 (m, 2H). LC/MS: Rt = 1.60 min, ES<+>424 (AA standard).

Example 15: ((1S,2R,3S,4R)-4-{4-[(1S)-2,3-Dihydro-1/-inden-1-ylamino]-7i/-

pyrrolo[2,3-(f]-pyrimidin-7-yl}-2,3-dihydroxycyclopentyl)methylsulfamate

(connection 1-17)

Step: ( 1R. 2S3R. 5S)- 3444( 1S)- 23- Dihvdro- li/- inden- 1- vlaminol- 7i/pyrrolo[ 2, 3-(/ 1- pyrimidine- 7- vl|- 5-( hvdroksvmetvl) svclopentan- l, 2- diol

[0222] A solution of (4αS,6R,7R,7αR)-6-{4-[(1S)-2,3-dihydro-1 H -inden-1-ylamino]-7 H -pyrrolo[2 ,3-(f|pyrimidin-7-yl}-2-(4-methoxyphenyl)-7-methylhexahydrocyclopenta[<i]-[1,3]dioxin-7-ol (312 mg, 0.594 mmol as prepared according to the procedure in example 1a-d, and (S)-(+)-1-aminoindane was used in step c) in THF (1.17 mL) and water (1.17 mL), added AcOH (3.51 mL, 61, 7 mmol) under nitrogen atmosphere. The mixture was stirred at room temperature overnight. Solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound as a white solid ( 182 mg, 76%).LC/MS: Rt = 0.85 min, ES<+>381 (FA standard).

Step b: (( 3aR. 4S. 6R. 6aS)- 6-{ 4- r( 1S)- 2. 3- Dihvdro- l//- inden- l- ylamino1- 7//pvrrolo[ 2, 3- yi - pvirimidin- 7- vl]- 2, 2- dimethyltetrahydro- 3ai/- cyclopenta[^] [ 1, 3] dioxol- 4- yl) methanol

[0223] A suspension with (1R,2S,3R,5S)-3-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2, 3-rf]pyrimidin-7-yl}-5-(hydroxymethyl)cyclopentane-1,2-diol (63.8 mg, 0.168 mmol) and 2,2-dimethoxypropane (0.103 mL, 0.838 mmol) in acetone (2, 10 mL) p-toluenesulfonic acid monohydrate (31.9 mg, 0.168 mmol) was added with rapid stirring. The resulting solution was stirred overnight. The reaction was quenched with a saturated aqueous sodium bicarbonate solution (1.00 mL) and the volume was reduced in vacuo. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 10 to 60% EtOAc in hexanes to give the title compound as a white solid (49.6 mg, 70%). LC/MS: Rt = 1.16 min, ES<+>421 (FA standard).

Step: (( lS. 2R. 3S. 4R)- 4-{ 4- r( lS)- 2. 3- Dihv( co- l^- inden4- vlaminol- 7//pvrrolo [ 2, 3 -( flpvrimidin- 7-vl]-2,3-dihydroxycyclopentyDmethylsulfamate

(connection 1-17)

[0224] A suspension with ((3αR,4S,6R,6αS)-6-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2 ,3-(i]pyrimidin-7-yl}-2,2-dimethyltetrahydro-3αi/-cyclopenta[d][1,3]dioxol-4-yl)methanol (45.9 mg, 0.109 mmol) and pyridine ( 0.0180 mL, 0.222 mmol) in AcCN (1.10 mL) and DCM (0.500 mL) at 0 °C under a nitrogen atmosphere was added dropwise a 2.00 M solution of chlorosulfonamide in AcCN (0.110 mL, 0.220 mmol, as prepared in lj). The suspension was stirred for 2 h and more 2.00 M of chlorosulfonamide in AcCN solution (0.150 mL, 3.00 mmol) was added. After 5 min the reaction was quenched with MeOH (1.00 mL) and the solvent was removed in vacuo The residue was purified by silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound as a white solid (23.1 mg, 46%).

'HNMR (400MHz, CD3OD, 5): 8.36 (s, 1H), 7.62 (d, J= 3.1 Hz, 1H), 7.43-7.33 (m, 4H), 7, 04 ( d, J = 3.0 Hz, 1H), 5.67 (br s, 1H), 5.25-5.20 (m, 1H), 4.61 (dd, J= 3.8, 9 .3 Hz, 1H), 4.48 (dd, J= 2.0, 9.9 Hz, 1H), 4.27-4.22 (m, 2H), 3.74 (s, 1H), 3 .27-3.20 (m, 1H), 3.13-3.05 (m, 1H), 3.02-2.90 (m, 1H), 2.87-2.77 (m, 1H) , 2.35-2.19 (m, 3H) ppm. LC/MS: Rt = 0.94 min, ES<+>460. (FA standard).

Example 16: ((1R,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-<i]-pyrimidine -7-yl}cyclopent-2-en-1-yl)methylsulfamate and ((1S,3S)-3-{4-[(1S)2,3-dihydro-1H-inden-1-ylaminol- 7//-pyrrolo[2,3-(f|pyrimidin-7-yl}cyclopentyl)methylsulfamate (compound 1-20 and I-1 1)

Step: ( lS. 2R. 3S. 5R)- 3-({ rferr-Butvirdimethvnsilvl] oxvlmetvn- 5-{ 4-[( lS)- 2. 3-dihydro- l//- inden- l- vlamino]- 7 //- pvrrolo[ 2, 3- yipyrimidine- 7-vl] svclopentan- 1, 2- diol

[0225] A solution of (1R,2S,3R,5S)-3-[4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7i7-pyrrolo[2,3 -(i]pyrimidin-7-yl}-5-(hydroxymethyl)cyclopentane-1,2-diol (166 mg, 0.436 mmol as prepared in Example 15a), tert -butyldimethylsilyl chloride (69.0 mg, 0.458 mmol), 1#-imidazole (44.6 mg, 0.654 mmol) in DMF (2.00 mL) was stirred under a nitrogen atmosphere.After 2 h, additional tert-butyldimethylsilyl chloride (6.00 mg, 0.0365 mmol) was added and the solution was stirred for 1 hour. The reaction was cooled with water and extracted with EtOAc. The combined organics were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was filtered through a plug of silica gel eluted with 60% EtOAc in hexanes to give the title compound as an off-white solid (179 mg, 83%) LC/MS: Rt = 1.51 min, ES<+>495 (FA standard).

Step b: ( 3aR . 4S . 6R . 6aS )- 4-({[ ter?- Butvl( dimetvnsilyl1oxymetvn- 6- ( 4[( 1S )- 2. 3-dihydro- li/- inden- 1- vlamino]- 7i/- pyrrolo[ 2, 3- 6ripvrimidin- 7-vl] tetrahydro- 3ai/- svclopenta[^ 1[ 1. 3] dioxol- 2- thione

[0226] A solution of (1S,2R,3S,5R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-{4-[(1S)-2,3-dihydro -1H-inden-1-ylamino]-7H-pyrrolo[2,3-tf|p<y>rimidm-7-yl}cyclopentane-1,2-diol (179 mg, 0.362 mmol) in DMF ( 2.00 mL) under a nitrogen atmosphere, 1,1'-thiocarbonyldiimidazole (72.3 mg, 0.406 mmol) was added and the solution was heated to 80 °C for 3 h. The solvent was removed and the residue was purified by silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes to give the title compound (158 mg, 81%). LC/MS: Rt = 2.24 min, ES<+>538 (FA standard).

Step c: 7 -\( 1R. 4R)- 4-(([ fer?- Butvl( dimetvl) silvl1oxvlmetvl) svclopent- 2- en- 1- yl1-A^-[( 1S)- 2. 3- dihydro- l//- inden- l- vl]- 7//- pyrrolo[ 2, 3-( i] pvrimidin- 4- amine

[0227] A solution of (3aR,4S,6R,6aS)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-{4-[(1 S )-2,3-dihydro - 1H-inden-1-ylamino]-7i7-pyrrolo[2,3-rf]pyrimidin-7-yl}tetrahydro-3aiH-cyclopenta[rf][1,3]dioxol-2-thione (138 mg, 0.257 mmol) in THF (0.860 mL) at 0 °C under a nitrogen atmosphere, 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine (0.147 mL, 0.793 mmol) was added dropwise. The solution was stirred for 10 minutes at 0 °C and then at room temperature for 5 hours. The solvent was removed and the residue purified by silica gel chromatography eluting with a gradient of 0 to 20% EtOAc in hexanes to give the title compound as a pure oil (-70% purity, 81.9 mg,

48%). LC/MS: Rt = 2.10 min, ES<+>462 (FA standard).

Step d: (( 1R. 4RV4-{ 4- r( lS)- 2. 3- Dihvdro- l//- inden- l- vlamino1- 7//- pyrrolor2. 3-^ pyrimidin- 7- yl svclopent- 2 - en-1-yl) methanol

[0228] A solution of 7-[(1R,4R)-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopent-2-en-1 -yl]-7V-[(l S)-2,3-dihydro- l/-inden-1-yl]-7//-pyrrolo[2,3-</]pyrimidin-4-amine (81.9 mg, 0.178 mmol) in pyridine (0.800 mL) and THF (0.800 mL) at 0 °C under a nitrogen atmosphere, pyridine hydrofluoride (0.0500 mL, 0.555 mol) was added dropwise. The solution was warmed to room temperature and stirred overnight. The reaction was quenched with a saturated aqueous sodium bicarbonate solution and diluted with EtOAc. The layers were separated and the aqueous layers were extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 5% MeOH in DCM to give the title compound as a white solid (-70% purity, 35.7 mg, 41%). LC/MS: Rt = 1.03 min, ES<+>347 (FA standard).

Step e: (( 1R, 4R)- 4- 14-[( 1 S)- 2, 3- Dihvdro- i7/- inden- 1- vlamino1- 7//- pvrrolo[ 2, 3-^l pvrimidin- 7 - yll svclopent- 2- en- 1 - vDmethylsulfamate (compound 1- 20)

[0229] A solution of ((1R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-tf |pyrimidin-7-yl}cyclopent-2-en-l-yl)methanol (35.7 mg, 0.103 mmol) and pyridine (0.0417 mL, 0.515 mmol) in AcCN (1.00 mL) at 0 °C under a nitrogen atmosphere, a 2.00 M solution of chlorosulfonamide in AcCN was added dropwise (0.260 mL, 0.520 mmol, as prepared in lj). The solution was stirred for 1 hour. The reaction was quenched with a saturated aqueous sodium bicarbonate solution and partitioned between water and EtOAc. The layers were separated and the aqueous layers were extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 5% MeOH in DCM to give the title compound as a solid (28.9 mg, 66%).<!>H NMR (400MHz, CDCb, 5): 8.36 (s, 1H), 7.35 (d, J= 7.2 Hz, 1H), 7.30-7.18 (m, 3H), 6.89 (d, J=3.6Hz, 1H), 6.32 (d,J= 3.5 Hz, 1H), 6.14-6.12 (m, 1H), 6.04-5.97 (m, 2H), 5.89 (br s, 1H), 4.19 (dd, J= 1.2, 6.0 Hz, 2H), 3.43-3.37 (m, 1H), 3.09-3.01 (m, 1H) , 2.98-2.90 (m, 1H), 2.77-2.69 (m, 1H), 2.46-2.39 (m, 1H), 2.07-1.93 (m, 3H) ppm. LC/MS: Rt = 1.24 min, ES<+>426 (FA standard).

Step f: ((1S,3S)-3-{4-[(1S)-2,3-dihydro-1#-^

pyrimidine-7-ylcyclopentyl)methylsulfamate (compound 1-11)

[0230] A suspension with ((1R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-(f |pyrimidin-7-yl)cyclopent-2-en-l-yl)methylsulfamate (17.3 mg, 0.0406 mmol) and 10% palladium on carbon (8.60 mg) in EtOAc (0.500 mL) were placed under hydrogen atmosphere. After 3 h, the flask was purged with nitrogen and the suspension filtered through diatomaceous earth eluted with EtOAc to give the title compound as a white solid (10.8 mg, 62%). <!>H NMR (400MHz, CDCb, 5): 8 .36 (s, 1H), 7.36 (d, J= 7.3 Hz, 1H), 7.29-7.15 (m, 3H), 7.00 (d, J= 3.4 Hz, 1H), 6.33 (d, J= 3.4 Hz, 1H), 5.91-5.87 (m, 1H), 5.41 (br s, 2H), 5.23-5.15 ( m, 2H), 4.26 (dd, J= 5.8, 9.8 Hz, 1H), 4.18 (dd, J= 6.2, 9.8 Hz, 1H), 3.09-3 .02 (m, 1H), 2.99-2.90 (m, 1H), 2.36-2.27 (m, 2H), 2.21-2.12 (m, 2H), 2.09 -1.93 (m, 3H), 1.66-1.57 (m, 1H) ppm. LC/MS: Rt = 1.24 min, ES<+>428 (FA standard).

Example 17: [(1S,2S,4R)-2-Hydroxy-4-(4-{[(5-methylisoxazol-3-yl)methyl]amino}-\H-pyrrolo[2,3-(f]pyridazine -1 -yl)cyclopentyl]methylsulfamate (compound 1-41)

Step a: Af-[( 5- Methylisoxazol-3- vl) metvl]- 7i/- pvrrolo[ 2, 3-^] pyrimidine- 4- amine

[0231] 4-Chloro-li H -pyrrolo[2,3-(f]pyrimidine (1.14 g, 7.43 mmol), (5-methyl-3-isoxazolyl)methylamine (1.00 g, 8, 92 mmol) and DIPEA (1.94 mL, 11.1 mmol) was added to 1-butanol (9.13 mL). The mixture was heated at 190 °C for 1600 seconds with MWI in three batches. The combined reactions were concentrated in in vacuo to give a brown oil. The residue was purified by silica gel chromatography eluting with EtOAc to give the title compound as a yellow solid (1.22 g, 72%). LC/MS: Rt = 0.63 min, ES <+>230.

(FA standard).

Step b: [( 1S . 2S . 4R )- 2-Hydroxy- 4-( 4-{ r( 5- methylisoxazole- 3- yl ) methylaminol- 1 / 7-pyrrolo-[ 2, 3-^ 1pyridazine- 1 - vDsvclopentylmethylsulfamate (compound I-41}

[0232] The title compound was prepared by following the procedure described in example 1d-k, and A^-[(5-methylisoxazol-3-yl)methyl]-7//-pyrrolo[2,3-(i]pyrimidine- 4-amine was used in step d.<!>H NMR (400 MHz, CD3OD, 5): 8.22 (s, 1H), 7.26 (d, J= 3.6 Hz, 1H), 6, 63 ( d, J = 3.6 Hz, 1H), 6.14 (s, 1H), 5.55-5.44 (m, 1H), 4.81 (s, 2H), 4.59 (br s, 1H), 4.42 (dd, J= 7.6, 9.6 Hz, 1H), 4.25 (dd, J= 7.4, 9.8 Hz, 1H), 2.91-2 .79 (m, 1H), 2.41 (s, 3H), 2.40-2.22 (m, 3H), 2.15-2.04 (m, 1H) ppm. LC/MS: Rt = 0.89 min, ES<+>423 (FA standard).

Example 18: [(1S,2S,4R)-4-(4-Anilino-1/-pyrrolo[2,3-^pyridazine 1-yl)-2-hydroxycyclopentyl]methylsulfamate (compound 1-39)

[0233] The title compound was prepared following the procedure described in 17a-b, and aniline was used in step a.<!>H NMR (400 MHz, CD 3 OD, 5): 8.18 (s, 1H), 7, 62 (d, J= 7.6 Hz, 2H), 7.31 (dd, J= 7.5, 8.4 Hz, 2H), 7.23 (d, J= 3.7 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.22 (d, J= 3.7 Hz, 1H), 5.50-5.39 (m, 1H), 4.46 (br s, 1H), 4.34 (dd, J=7.6, 7.6 Hz, 1H), 4.16 (dd, J= 7.4, 7.4 Hz, 1H), 2.89-2 .73 (m, 1H), 2.37-2.15 (m, 3H), 2.09-1.97 (m, 1H) ppm. LC/MS: Rt = 1.03 min, ES<+>404 (FA standard).

Example 19: [(1S,2S,4R)-2-Hydroxy-4-(4-{[2-(trifluoromethyl)benzyl]amino)-\H-pyrrolo-[2,3-<f]pyridazine-1 -yl)cyclopentyl]methylsulfamate (compound I-47)

[0234] The title compound was prepared following the procedure described in Example 17a-b, and 2-(trifluoromethyl)benzylamine was used in step a.<!>H NMR (400 MHz, CD 3 OD, 5): 8.08 (s , 1H), 7.66 (d, J= 7.7 Hz, 1H), 7.47 (d, J= 4.0 Hz, 2H), 7.42-7.34 (m, 1H), 7 .19 (d, J= 3.7 Hz, 1H), 6.60 (d, J= 3.2 Hz, 1H), 5.50-5.36 (m, 1H), 4.94 (s, 1H), 4.45 (br s, 1H), 4.34 (dd, J= 7.5, 7.6 Hz, 1H), 4.16 (dd, J= 7.4, 7.4 Hz, 1H), 3.27 (q, J=1.6, 3.3 Hz, 1H), 2.94-2.73 (m, 1H), 2.35-2.15 (m, 3H), 2 .06-1.96 (m, 1H) ppm. LC/MS: Rt = 1.25 min, ES<+>486 (FA standard).

Example 20: ((1S,2S,4R)-4-{4-[(Cyclopropylmethyl)amino]-7/-pyrrolo[2,3-cT|pyrimidin-7-yl]-2-hydroxycyclopentyl)methylsulfamate (compound 1-25)

Step a: ( 1S , 2S , 4R )- 4-{ 4-[( Cyclopropylmethyl)amino]- 7i/- pyrrolo[ 2. 3-( i ]pyrimidin-7-yl]- 2-( hydroxymethyl)cyclopentanol

[0235] The title compound was prepared by following the procedure described in Example la-g, and cyclopropylmethylamine was used in step c. LC/MS: Rt = 0.90 min, ES<+>303 (FA standard).

Step b: 7-[( 1R , 3S , 4S )- 3-{[ fe^-Butyl(dimethyl)silyl]oxyl- 4-( {[ tert-Butyl(dimethyl)silyl] oxyl)methyl)sylpentyl]- 7V -( svclopropvlmetvl)- 7//pvrrolo [ 2. 3 -^ pvrimidin- 4- amine

[0236] (1S,2S,4R)-4-{4-[(Cyclopropylmethyl)amino]-7iH-pyrrolo[2,3-(f]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol (280 mg, 0.923 mmol) was stirred in DMF (3.00 mL). tert-Butyldimethylsilyl chloride (698 mg, 4.63 mmol) was added followed by 1H-imidazole (142 mg, 2.08 mmol) and 4-(dimethylamino)pyridine (10.0 mg, 0.0818 mmol). The reaction was stirred for 1 h and then diluted with water and extracted with EtOAc (3 x 15 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting oil was dried under high vacuum overnight. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 15% EtOAc in hexanes to give the title compound (203 mg, 41%). LC/MS: Rt = 2.16 min, ES<+>531 (FA standard).

Step c: (( 1S . 2S . 4R )- 2-{ rter?- Butvl( dimethylsilyl1oxvl- 4-{ 4-[( svclopropvlmeM) amino]- 7//- pvrrolo [ 2. 3-( f| pvrimidin- 7 -

howl| svklopentvDmethanol

[0237] 7-[(1R,3S,4S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]- N-(cyclopropylmethyl)-7iH-pyrrolo[2,3-</]pyrimidin-4-amine (100 mg, 0.188 mmol) was dissolved in THF (0.900 mL) and pyridine (0.900 mL). Pyridine hydrofluoride (7 drops) was added and the reaction was stirred for 5 hours. Additional pyridine hydrofluoride (3 drops) was added and the reaction was stirred for 2 hours before being quenched with a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted using EtOAc (3x10 mL), and the combined organic extracts were dried over MgSO/t, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes to give the title compound (47.0 mg, 50%). LC/MS: Rt = 1.53 min, ES<+>417 (FA standard).

Step d: (( 1S . 2S . 4R )- 2-{[ ter ?- Butyridimethylenesilyl] oxv )- 4-{ 4-[( cyclopropylmethyl) amino]- 7i /- pyrrolo[ 2, 3-( i] pyrimidine- 7-ylsvclopentvDmethyl sulfamate

[0238] ((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy)-4-{4-[(cyclopropylmethyl)amino]-7 H -pyrrolo[2,3- (i]pyrimidin-7-yl}cyclopentyl)methanol (74.0 mg, 0.178 mmol) was dissolved in AcCN (3.50 mL) and cooled to 0 °C. TEA (0.0500 mL, 0.355 mmol) was added followed by a 2.00 M solution of chlorosulfonamide in AcCN (0.178 mL, 0.356 mmol, as prepared in lj). The reaction was stirred for 2 h, quenched with MeOH and concentrated in vacuo. The material was carried over to the next step without further purification. LC/MS: Rt =1.51 min, ES<+>496 (FA standard).

Step e: (( 1S . 2S . 4R )- 4-{ 4- r( Cyclopropylmethyl)amino1- 7i/- pyrrolor2. 3-<fl pvirimidin- 7-yl| - 2- hydroxyscyclopentyl) methylsulfamate ( compound I-25 }

[0239] ((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(cyclopropylmethyl)amino]-7i H -pyrrolo[2,3-(i ]pyrimidin-7-yl}cyclopentyl)methylsulfamate (88.0 mg, 0.178 mmol) was dissolved in THF (1.00 mL) and pyridine (3.00 mL).Pyridine hydrofluoride (12 drops) was added and the reaction was stirred for 3 h. The reaction was quenched using a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with EtOAc (3x10 mL), and the combined organic extracts were dried over MgSO/t, filtered, and concentrated in vacuo. The residue was purified by silica gel -chromatography eluting with 5% MeOH in DCM The compound was repurified by silica gel chromatography eluting with 10% MeOH in DCM to give the title compound (3.00 mg, 4.4%).<!>H NMR (400 MHz , CD3OD, 5): 8.05 (s, 1H), 7.15 (d, J= 3.6 Hz, 1H), 6.59 (d, J= 3.6 Hz, 1H), 5.45 -5.32 (m, 1H), 4.56 (br s, 1H), 4.45 (br s, 1H), 4.33 (dd, J = 7.6, 7.6 Hz, 1H), 4.15 (dd, J= 7.4, 7.4 Hz, 1H), 3.34 (d, J= 6.9 Hz, 2H), 2.83-2.68 (m, 1H), 2.35-2.08 (m, 3H), 2.05-1.93 (m, 1H), 1.33-1.03 (m, 3H), 0.93-0.77 (m, 1H ) ppm. LC/MS: Rt = 0.85 min, ES<+>382 (FA standard).

Example 21: ((1S,2S,4R)-4-{4-[(4-Chlorobenzyl)oxy]-7H-pyrrolo[2,3-^pyrimidin-7-yl]-2-hydroxycyclopentyl)methylsulfamate (compound 1-34)

Step a: 4-[( 4-Chlorobenzvl) oxv]- 7//- pvrrolo[ 2. 3-^] pyrimidine

[0240] A 0.375 M solution of aqueous potassium hydroxide (26.2 mL, 9.83 mmol) was added to (4-chlorophenyl)methanol (464 mg, 3.26 mmol), and the mixture was heated to 80 °C for 30 minutes. Then 4-chloro-1 H -pyrrolo[2,3-^]pyrimidine (500 mg, 3.26 mmol) was added and the mixture was refluxed at 130 °C. After 6 h, additional (4-chlorophenyl)methanol (100 g, 0.701 mmol) was added and the solution was heated to 115 °C overnight. The reaction was cooled to room temperature and diluted with water. The solution was then extracted with EtOAc (2x) and DCM (2x). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude oil was purified by silica gel chromatography eluting with a gradient of 5 to 30% EtOAc in DCM to give the product as a white solid (210 mg, 25%). LC/MS: Rt = 1.72 min, ES<+>260. (FA standard).

Step b: (( 1S . 2S . 4R )- 4-( 4-[ r 4-Chlorobenzyl) oxyl- 7//- pvirrolo[ 2. 3-^ 1pyrimidine- 7-yl]- 2- hydroxycyclopentyl) methylsulfamate (compound 1 - 34)

[0241] The title compound was prepared by following the procedure described in Example 1d-g and then Example 2i-j, and 4-[(4-Chlorobenzyl)oxy]-7i7-pyrrolo[2,3-d]pyrimidine was used in step ld.<*>H NMR (400 MHz, CD3OD, 5): 8.35 (s, 1H), 7.51-7.34 (m, 5H), 6.56 (d, J= 3.5 Hz, 1H), 5.55 (s, 2H), 5.54-5.46 (m, 1H), 4.52-4.48 (m, 1H), 4.37 (dd, J= 7, 8, 10.0 Hz, 1H), 4.20 (dd, J= 7.3, 9.8 Hz, 1H), 2.90-2.80 (m, 1H), 2.34-2.20 (m, 3H), 2.11-2.03 (m, 1H) ppm. LC/MS: Rt = 1.81 min, ES<+>453 (FA standard).

Example 22: {(1S,2S,4R)-4-[4-(Benzylsulfanyl)-7i/-pyrrolo[2,3-^]pyrimidin-7-yl]-2-hydroxycyclopentyl}methylsulfamate (compound 1-32)

[0242] The title compound was prepared by following the procedure described in Examples 2a-d and g-j. <!>H NMR (400 MHz, CD 3 OD, 5): 8.54 (s, 1H), 7.45-7.36 (m, 3H), 7.28-7.14 (m, 3H), 6.47 (d, J= 3.6 Hz, 1H), 5.51-5.43 (m, 1H), 4, 58 (s, 2H), 4.49-4.45 (m, 1H), 4.33 (dd, J= 7.6, 9.7 Hz, 1H), 4.16 (dd, J= 7, 3, 9.7 Hz, 1H), 2.87-2.78 (m, 1H), 2.62 (s, 2H), 2.32-2.15 (m, 3H), 2.08-2 .01 (m, 1H) ppm. LC/MS: Rt = 1.97 min, ES<+>435 (FA standard).

Example 23: ((1S,2S,4R)-4-{4-[(4-Chlorobenzyl)amino]-7H-pyrrolo[2,3-<|pyrimid-7-yl}-2-hydroxycyclopentyl)methylsulfamate (connection 1-45)

[0243] The title compound was prepared by following the procedure described in Example 2a-j, and 4-chlorobenzylamine was used in step f. 1H NMR (400 MHz, CD 3 OD, 5): 8.10 (s, 1H), 7 .34-7.28 (m, 4H), 7.21 (d, .7=3.6 Hz, 1H), 6.59 (d,J=3.6 Hz, 1H), 5.47-5 .39 (m, 1H), 4.73 (s, 2H), 4.50-4.48 (m, 1H), 4.25 (dd, J= 8.3, 9.9 Hz, 1H), 4.09 (dd, J= 6.8, 10.0 Hz, 1H), 3.35-3.33 (m, 2H), 2.81-2.71 (m, 1H), 2.35- 2.29 (m, 1H), 2.26-2.15 (m, 2H), 2.02-1-96 (m, 1H) ppm. LC/MS: Rt = 5.39 min, ES<+>452 (FA standard, long purification method)

Example 24: ((1S,2S,4R)-4-{4-[(3-Chlorobenzyl)amino]-777-pyrrolo[2,3-^]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (compound 1-51)

[0244] The title compound was prepared by following the procedure as

described in example 2a-j, and 3-chlorobenzylamine was used in step f.<*>H NMR (400 MHz, CD3OD, 5): 8.22 (s, 1H), 7.44-7.31 (m, 5H), 6.78 (d, J= 3.6 Hz, 1H), 5.56-5.48 (m, 1H), 4.82 (s, 2H), 4.56-4.52 (m , 1H), 4.42 (dd, J= 7.5, 9.8 Hz, 1H), 4.25 (dd, J= 7.3, 9.8 Hz, 1H), 2.92-2, 83 (m, 1H), 2.42-2.26 (m, 3H), 2.15-2.08 (m, 1H) ppm. LC/MS: Rt = 1.51 min, ES<+>452 (FA standard).

Example 25: ((1S,2S,4R)-4-{4-[(4-Chloro-2-methylbenzyl)amino]-777-pyrrolo[2,3-^-pyrimidin-7-yl}-2-hydroxycyclopentyl )methylsulfamate (compound 1-48)

[0245] The title compound was prepared following the procedure described in Example 2a-j, and 4-chloro-2-methylbenzylamine was used in step f. <!>H NMR (400 MHz, CD 3 OD, 5): 8.12 ( s, 1H), 7.26-7.21 (m, 3H), 7.14-7.11 (m, 1H), 6.66 (d, J= 3.5 Hz, 1H), 5.49 -5.41 (m, 1H), 4.69 (s, 2H), 4.50-4.47 (m, 1H), 4.36 (dd, J= 7.5, 9.8 Hz, 1H ), 4.19

(dd, y = 7.5, 9.8 Hz, 1H), 2.86-2.76 (m, 1H), 2.36 (s, 3H), 2.33-2.19 (m, 3H ), 2.08-2.01 (m, 1H) ppm. LC/MS: Rt = 1.11 min, ES<+>466 (FA standard).

Example 26: ((1S,2S,4R)-2-Hydroxy-4-{4-[(2-methoxybenzyl)amino]-7 H -pyrrolo[2,3-<y>j -pyrimidin-7-yl }cyclopentyl)methylsulfamate (compound 1-43)

[0246] The title compound was prepared following the procedure described in Example 2a-j, and 2-methoxybenzylamine was used in step f. <!>H NMR (400 MHz, CD 3 OD, 5): 8.08 (s, 1H) , 7.24-7.18 (m, 3H), 6.96 (d, J= 7.8 Hz, 1H), 6.85 ( ate, J= 0.8, 7.3 Hz, 1H), 6.61 (d, J= 3.5 Hz, 1H), 5.47-5.39 (m, 1H), 4.72 (s, 2H), 4.50-4.46 (m, 1H) , 4.36 (dd, 7 = 7.5, 9.8 Hz, 1H), 4.19 (dd, J = 7.3, 9.8 Hz, 1H), 3.87 (s, 3H), 2, 84-2.75 (m, 1H), 2.35-2.18 (m, 3H), 2.06-1.99 (m, 1H) ppm. LC/MS: Rt = 1.16 min, ES<+>448 (FA standard).

Example 27: ((1S,2S,4R)-4-{4-[(3,4-Dichlorobenzyl)amino]-7 H -pyrrolo[2,3-<y>]pyrimidin-7-yl}-2 -hydroxycyclopentyl)methylsulfamate (compound I-24)

(0247) The title compound was prepared by following the procedure described in Example 2a-j, and 3,4-dichlorobenzylamine was used in step f. <!>H NMR (400 MHz, CD 3 OD, 5): 8.15 (s, 1H), 7.51 (d, J= 2.0 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.30-7.27 (m, 2H), 6, 65 (d, y = 3.5 Hz, 1H), 5.48-5.41 (m, 1H), 4.74 (s, 2H), 4.49 (t, J = 4.0 Hz, 1H ), 4.37 (dd, y = 7.5, 9.8 Hz, 1H), 4.20 (dd, J = 7.5, 9.8 Hz, 1H), 2.86-2.77 (m, 1H), 2.36-2.20 (m, 3H), 2.08-2.01 (m, 1H) ppm. LC/MS: Rt = 1.16 min, ES<+>486 (FA standard ).

Example 28: ((1S,2S,4R)-2-Hydroxy-4-{4-[(1S)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-7 H -pyrrolo[2,3 -(i]pyrimidin-7-yl}cyclopentyl)methylsulfamate

(compound I 37)

[0248] The title compound was prepared by following the procedure described in Example 2a-j, and (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine was used in step f.<!>H NMR

(400 MHz, CD3OD, 5): 8.16 (s, 1H), 7.26-7.07 (m, 5H), 6.63 (d, J= 3.5 Hz, 1H), 5.56 -5.50 (m, 1H), 5.49-5.41 (m, 1H), 4.50 (m, 1H), 4.38 (dd, J= 7.5, 9.8 Hz, 1H ), 4.20 (dd, J = 7.3, 9.8 Hz, 1H), 2.93-2.76 (m, 3H), 2.37-2.20 (m, 3H), 2, 17-1.82 (m, 5H) ppm. LC/MS: Rt = 1.29 min, ES<+>458 (FA standard).

Example 29: ((1S,2R,3S,4R)-4-{4-[(4-Chlorobenzyl)amino]-7 H -pyrrolo[2,3-<i]pyrimidin-7-yl}-2, 3-dihydroxycyclopentyl)methylsulfamate (compound 1-22)

[0249] The title compound was prepared following the procedure described in Examples 2a-d and g-j, and 4-chlorobenzylamine was used in step f. <!>H NMR (300 MHz, CD 3 OD, 5): 8.11 (s, 1H), 7.34-7.21 (m, 5H), 6.60 (d, J= 3.6 Hz, 1H), 5.06-4.97 (m, 1H), 4.74 (s , 2H),4.51 (dd, 7= 3.6, 9.2 Hz, 1H), 4.40 (dd, 7 =8.0, 9.6 Hz, 1H), 4.18-4, 14 (m, 2H), 2.88-2.78 (m, 1H), 2.23-2.02 (m, 2H) ppm. LC /MS: R =1.46 min, ES<+>468 (AA standard).

Example 30: ((1S,2S,4R)-4-{6-[(4-Chlorobenzyl)amino]-9H-purin-9-yl}-2-hydroxycyclopentyl)methylsulfamate (compound 1-23)

[0250] The title compound was prepared by following the procedure described in Example la-f and Example 2h-j, and 4-chlorobenzylamine and 6-chloro-9//-purine were used in step le.<!>HNMR (300 MHz , CD3OD, 5): 8.23 (s, 1H), 8.14 (s, 1H), 7.35-7.25 (m, 4H), 5.31-5.22 (m, 1H), 4.79 (s, 2H), 4.51-4.49 (br s, 1H), 4.37 (dd, J= 7.5, 9.6 Hz, 1H), 4.23-4.17 (m, 1H), 2.93-2.87 (m, 1H) 2.47-2.30 (m, 2H), 2.28-2.10 (m, 2H) ppm. LC/MS: Rt = 1.42 min, ES<+>453 (AA standard).

Example 31: [(1S,2S,4R)-2-Hydroxy-4-(4-methyl-7/-pyrrolo[2,3-<|pyrimidin-7-yl)cyclopentyl]methylsulfamate (compound 1-46)

Step a: 4- Methyl- 7//- pvrrolo[ 2. 3-^] pyrimidine

[0251] A 3.00 M solution of magnesium chloride in THF (13.0 mL, 39.0 mmol) was added dropwise to a stirred solution of 4-chloro-i//-pyrrolo[2,3-(f| pyrimidine (2.50 g, 16.3 mmol) and ferric acetylacetonate (700 mg 1.98 mmol) in THF (30.0 mL) under an argon atmosphere. The resulting reaction mixture was stirred at room temperature for 8 h. The mixture was poured into a ice mixture (100 mL) and ammonium chloride (1.00 g) and the mixture was extracted with chloroform. Volatiles were removed in vacuo and C-18 column chromatography eluting with a gradient of 0 to 60% AcCN in water with 0.1% AA gave the title compound (1.50 g, 69%) LC/MS: R = 0.94 min, ES<+>134 (AA standard).

Step b: [( 1 S . 2 S . 4 R )- 2- Hydroxiv- 4-( 4- methyl- 7//- pvrrolo[ 2. 3- ypyrimidine- 7-vDscyclopentylmethylsulfamate (compound 1- 46)

[0252] The title compound was prepared following the procedure described in Example 1a-k, and 4-methyl-7i/-pyrrolo[2,3-<f]pyrimidine was used in step c.<!>H NMR (CD 3 OD, 300 MHz, 5): 8.69 (s, 1H), 7.68 (d, J= 3.6 Hz, 1H), 6.82 (d, J= 3.6 Hz, 1H), 5.63 -5.51 (m, 1H), 4.53 4.49 (m, 1H), 4.37 (dd, J= 7-5, 9.9 Hz, 1H), 4.20 (dd, J= 7.5, 9.9 Hz, 1H), 2.90-2.80 (m, 1H), 2.77 (s, 3H), 2.36-2.05 (m, 4H) ppm. LC/MS: Rt = 0.50 min, ES<+>327 (FA standard).

Example 32: {(1S,2S,4R)-2-Hydroxy-4-[4-(2-phenylethyl)-7H-pyrrolo[2,3-y]pyrimidin-7-yl]-cyclopentyl}methylsulfamate (connection 1-28)

[0253] The title compound was prepared by following the procedure described in Example 31 a-b, and chloro(2-phenylethyl)magnesium was used in step a.<*>H NMR (CD 3 OD, 300 MHz, 5): 8.62 (s , 1H), 7.48 (d, J= 3.9 Hz, 1H), 7.19-7.09 (m, 5H), 6.57 (d, J= 3.9 Hz, 1H), 5 .55-5.46 (m, 1H), 4.49-4.46 (m,lH), 4.35 (dd, J=7.8, 9.6 Hz, 1H), 4.18 (dd , J = 7.5, 9.6 Hz, 1H), 3.28-3.24 (m, 2H), 3.10-3.04 (m, 2H), 2.88-2.80 (m , 1H), 2.31-2.01 (m, 4H) ppm. LC/MS: Rt = 1.56 min, ES<+>417 (AA standard).

Example 33: [(1S,2S,4R)-2-Hydroxy-4-[4-(2-methyl-2-phenylpropyl)-7/-pyrrolo[2,3-^]-pyrimidin-7-yl] cyclopentyl}methylsulfamate (compound 1-50)

[0254] The title compound was prepared following the procedure described in Example 31 a-b, and chloro(2-methyl-2-phenylpropyl)magnesium was used in step a.<!>H NMR (400 MHz, CD 3 OD, 5): 8 .62 (s, 1H), 7.37-7.34 (m, 2H), 7.25-7.21 (m, 2H), 7.16-7.12 (m, 1H), 6.15 (d, 1H), 5.56-5.47 (m, 1H), 4.49-4.48 (br s, 1H), 4.37 (dd, J= 7.6, 9.6 Hz, 1H), 4.22-4.17 (m, 1H), 2.93-2.87 (m, 1H), 2.89-2.80 (m, 1H), 2.31-2.19 ( m, 3H), 2.07-2.00 (m, 1H), 1.43 (s, 6H) ppm. LC/MS: Rt = 1.59 min, ES<+>445 (AA standard).

Example 34: {(1S,2S,4R)-4-[4-(Acetylamino)-7H/-pyrrolo[2,3-^]pyrimidin-7-yl]-2-hydroxycyclopentyljmethylsulfamate and [(1S,2S, 4R)-4-(4-amino-7i/-pyrrolo[2,3-<i]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate

(connection 1-9 and 1-18)

Step a: ( 1S . 2S . 4R )- 4-( 4- Amino- 7//- pyrrolo[ 2. 3-^ 1Pvrimidin- 7- vl )- 2-(hvdroxvmetvDcyclopentanol

[0255] A solution of 7N-(2,4-dimethoxybenzyl)-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[(f|[1,3]dioxin-6-yl ]-7i/-pyrrolo[2,3-(i]pyrimidin-4-amine (123 mg, 0.238 mmol was prepared following the procedure described in Examples la-f, and 2,4 dimethoxybenzylamine was used in step c) and AcOH (1.00 mL, 17.6 mmol) in water (0.500 mL) and THF (0.500 mL) were stirred at room temperature overnight.The reaction mixture was concentrated in vacuo and purified by silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM gave the title compound (43.0 mg, 73%) LC/MS: Rt = 0.15 min, ES<+>249 (FA standard).

Step b: ( 1S . 2S . 4R )- 4-( 4- Amino- 7//- pyrrolo[ 2 . 3-^ 1Pvrimidine- 7- vl )- 2-(([ tert -butvl( dimethylvl) silvl] oxy | methyl) sclopentanol

[0256] A solution of (1S,2S,4R)-4-(4-amino-7iH-pyrrolo[2,3-(i]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol (43.0 mg, 0.173 mmol) and imidazole (25.0 mg, 0.367 mmol) in dry DMF (2.00 mL) at 0 °C was added tert-butyldimethylsilyl chloride (29.0 mg, 0.192 mmol). The solution was stirred at room temperature for 2 h and concentrated in vacuo, the residue was dissolved in water and extracted with EtOAc.The combined organic extracts were dried over MgSO/t, filtered and concentrated in vacuo to give the title compound (50.8 mg, 81%) which was taken without further cleanup LC/MS: Rt = 1.38 min, ES<+>364 (FA standard).

Step c: ( 1S . 2S . 4R )- 4- r 4 -(Acetylamino)- 7if - pvrrolor 2 . 3-^ 1Primidine-7- val1- 2-({[tert-butyl(dimethyl)silyloxyvlmethyl)sylclopentyl acetate

[0257] A solution of (1S,2S,4R)-4-(4-amino-7i7-pyrrolo[2,3-fr]pyrimidin-7-yl)-2-({[tert-butyl(dimethyl) To silyl]oxy}methyl)cyclopentanol (125 mg, 0.345 mmol) in pyridine (2.00 mL) at 0 °C was added acid anhydride (0.380 mL, 4.03 mmol). The solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM and water. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes to give the title compound (47.8 mg, 31%). LC/MS: Rt = 1.68 min, ES<+>447 (FA standard).

Step d: ( 1 S . 2 S . 4 R )- 4- r 4 -(Acetvlamino)- 7 i / - pvrrolo[ 2. 3- 6 npvrimidin- 7- vl 1- 2-( hydroxymethyl<y>Dscyclopentyl acetate

[0258] A solution of (1S,2S,4R)-4-[4-(acetylamino)-7iH-pyrrolo[2,3-(f]pyrimidin-7-yl)-2-({[ter; -butyl(dimethyl)silyl]oxy}methyl)cyclopentyl acetate (47.0 mg, 0.105 mmol) in a mixture of THF (2.00 mL) and pyridine (2.00 mL) was added pyridine hydrofluoride (10 drops). After 2 h, additional pyridine hydrofluoride (15 drops) was added and the solution was stirred for an additional 2 h. The reaction was quenched by the addition of a saturated aqueous sodium bicarbonate solution and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to give the title compound (29.0 mg, 83%). LC/MS: Rt = 0.76 min, ES<+>333 (FA standard).

Step e: (1S.2S.4R)-4-r4-(Acetylamino)-7//- pyrrolor2. 3- 6-pyrimidin- 7- vl1- 2-{[( aminosulfonvDoxvlmetvDsvclopentyl acetate

[0259] A solution of (1S,2S,4R)-4-[4-(acetylamino)-7if-pyrrolo[2,3-(f|pyrimidin-7-yl]-2-(hydroxymethyl)cyclopentyl acetate (63 .0 mg, 0.190 mmol) and pyridine (0.0800 mL, 0.989 mmol) in AcCN (5.00 mL) at 0 °C was stirred for 15 min. A 0.641 M solution of chlorosulfonamide in AcCN (0.640 mL, 0.410 mmol , as prepared in lj) was then slowly added. After 2 h, another portion of a chlorosulfonamide solution (0.72 mL, 0.462 mmol) was added and the reaction was stirred for 1 h. The reaction was then concentrated in vacuo and the residue purified with silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to give the title compound (78.0 mg, 100%). LC/MS: R = 0.81 min, ES<+>412 (FA standard) .

Step f: {( 1 S, 2S, 4R)- 4-[ 4-(Acetvlamino)- 7//- pvrrolo[ 2 3-^] pyrimidine- 7- vl 1- 2-hydroxyvsvclopentvl] methylsulfamate and [( 1S. 2S. 4R)- 4-( 4-amino- 7i/pyrrolo-[ 2, 3-^ 1pyrimidin- 7- vl)- 2- hydroxyvsvclopentvl1metvlsulfamate

(connection 1-9 and 1-18)

[0260] An unmixed (1S,2S,4R)-4-[4-(acetylamino)-7/-pyrrolo[2,3-^]pyrimidin-7-yl]-2-{[(aminosulfonyl)oxy ]methyl}cyclopentyl acetate (78.0 mg, 0.190 mmol) was added to a 7 M solution of ammonia in MeOH (5.00 mL) stirred at room temperature overnight. LC/MS showed partial conversion to the intermediate mono-acetylated compound, the desired product and some starting material remained. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase chromatography to give [(1S,2S,4R)-4-[4-(acetylamino)-7Jf-pyrrolo[2,3-^]pyrimidin-7-yl] -2-Hydroxycyclopentyljmethylsulfamate (0.900 mg, 1.3%) and [(1S,2S,4R)-4-(4-amino-7iH-pyrrolo[2,3-^]pyrimidin-7-yl)-2- hydroxycyclopentyl]methylsulfamate (6.50 mg, 11%). Analytical data for {(1S,2S,4R)-4-[4-(acetylamino)-7H/-pyrrolo[2,3-<|pyrimidin-7-yl]-2-hydroxycyclopentyl lmethylsulfamate (compound 1-9):< !>H NMR (400 MHz, CD 3 OD, δ): 8.48 (s, 1H), 7.47 (d, J= 3.8 Hz, 1H), 6.82 ( d, J= 3.8, 1H), 5.65-5.48 (m, 1H), 4.60-4.45 (m, 1H), 4.40-4.27 (m, 1H), 4.24-4.11 ( m, 1H), 2.98-2.80 (m, 1H), 2.42-2.13 (m, 6H), 2.18-1.93 (m, 1H) ppm. LC/MS: R = 0.98 min, ES<+>370. (FA standard). Analytical data for [(1S,2S,4R)-4-(4-amino-7//-pyrrolo[2,3-^]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (compound 1-18) :<!>H NMR (400 MHz, CD3OD, 5): 8.09 (s, 1H), 7.30 (d, .7=3.8 Hz, 1H), 6.66 (d, .7= 3.5 Hz, 1H), 5.51-5.41 (m, 1H), 4.51-4.48 (m, 1H), 4.39-4.33 (m, 1H), 4.21 -4.16 (m, 1H), 2.85-2.79 (m, 1H), 2.33-2.18 (m, 3H), 2.09-2.00 (m, 1H) ppm. LC/MS: R = 0.85 min, ES<+>328 (FA standard).

Example 35: ((1S,2S,4R)-4-{4-[(1,3-Benzodioxol-5-ylmethyl)amino]-77 H -pyrrolo[2,3-(7]-pyrimidin-7-yl }-2-hydroxycyclopentyl)methylsulfamate compound (I-26)

[0261 ] The title compound was prepared following the procedure described in Example 2a-j, and l-(l,3-benzodioxol-5-yl)methanamine was used in step f. 'H-NMR (400 MHz, CD3OD, 5 ): 8.09 (s, 1H), 7.15 (d, J= 3.6 Hz, 1H), 6.81 (s, 1H), 6.79 (d, J= 9.9 Hz, 1H ), 6.70 (d, J= 7.8 Hz, 1H), 6.56 (d, J= 3.6 Hz, 1H), 5.85 (s, 2H), 5.45-5.35 (m, 1H),

4.62 (s, 2H), 4.49-4.42 (m, 1H), 4.33 (dd, J= 7.6, 7-6 Hz, 1H), 4.16 (dd, J= 7.3, 7.3 Hz, 1H), 2.86-2.70 (m, 1H), 2.35-2.10 (m, 3H), 2.05-1.94 (m, 1H) ppm. LC/MS: R =1.07 min, ES<+>462 (FA standard).

Example 36: ((1S,2S,4R)-2-Hydroxy-4-{4-[(1-naphthylmethyl)amino]-77H-pyrrolo[2,3-^-pyrimidin-7-yl}cyclopentyl)methylsulfamate (connection 1-38)

[0262] The title compound was prepared by following the procedure described in Example 2a-j, and l-(l-naphthyl)methanamine was used in step f. <!>H NMR (400 MHz, CD 3 OD, 5): 8.13 (s, 1H), 8.11-8.05 (m, 1H), 7.89-7.84 (m, 1H), 7.77 (d, J= 8.2 Hz, 1H), 7, 52-7.43 (m, 3H), 7.42-7.35 (m, 1H), 7.15 (d, J= 3.6 Hz, 1H), 6.56 ( d, J= 3, 3 Hz, 1H), 5.45-5.37 (m, 1H), 5.19 (s, 2H), 4.48-4.42 (m, 1H), 4.34 (dd, J= 7 .6, 7.6 Hz, 1H), 4.17

(dd, J= 7.3, 7.4 Hz, 1H), 2.83-2.71 (m, 1H), 2.35-2.15 (m, 3H), 2.06-1.96 (m, 1H) ppm. LC/MS: Rt = 1.24 min, 468 ES<+>(FA standard).

Example 37: [(1S,2S,4R)-2-Hydroxy-4-(4-{[4-(trifluoromethyl)benzyl]amino}-7Jf/-

pyrrolo-[2,3-<i]pyrimidin-7-yl)cyclopentyl]methylsulfamate (compound 1-8)

[0263] The title compound was prepared by following the procedure described in Example 2a-j, and 1-[4-(trifluoromethyl)phenyl]methanamine was used in step f.<!>H NMR (CD 3 OD, 400 MHz, 5): 8.08 (s, 1H), 7.56 ( d, J= 8.2 Hz, 2H), 7.48 (d, J= 8.2 Hz, 2H), 7.18 ( d, J= 3 .5 Hz, 1H), 6.58 (d, J= 3.6 Hz, 1H), 5.43-5.34 (m, 1H), 4.80 (s, 2H), 4.45 (br s, 1H), 4.33 (dd, J= 2.1, 7.6 Hz, 1H), 4.16 (dd, J= 2.3, 7.4 Hz, 1H), 2.81-2 .72 (m, 1H), 2.31-2.10 (m, 3H), 2.05-1.97 (m, 1H) ppm. LC/MS: Rt =1.33 min, ES<+>486 (FA standard).

Example 38: [(1S,2S,4R)-4-(4-{[4-Chloro-2-(trifluoromethyl)benzyl]amino}-77/-

pyrrolo[2,3-^pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate

(compound I 42)

[0264] The title compound was prepared following the procedure described in Example 2a-j, and 1-[4-chloro-2-(trifluoromethyl)phenyl]methanamine was used in step f.<!>H NMR (CD 3 OD, 400 MHz , 5): 8.11 (s, 1H), 7.70 (s, 1H), 7.65-7.46 (m, 2H), 7.23 (d, J = 3.6 Hz, 1H) , 6.61 (d, J= 3.4 Hz, 1H), 5.48-5.39 (m, 1H), 4.93 (s, 2H), 4.49 (br s, 1H), 4 .36 (dd, .7=2.1, 7.6 Hz, 1H), 4.20 (dd, J= 2.3, 7.4 Hz, 1H), 2.87-2.74 (m, 1H), 2.38-2.12 (m, 3H), 2.09-1.97 (m, 1H) ppm. LC/MS: Rt = 1.29 min, ES<+>520 (FA standard).

Example 39: ((1S,2S,4R)-4-[4-[(2,4-Dichlorobenzyl)amino]-777-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (connection I-19)

[0265] The title compound was prepared by following the procedure described in Example 2a-j, and 1-(2,4-dichlorophenyl)methanamine was used in step f. <!>H NMR (CD 3 OD, 400 MHz, 5): 8 .10 (s, 1H), 7.46 (s, 1H), 7.32 (d, J= 8.3 Hz, 1H), 7.29-7.20 (m, 2H), 6.61 ( d, J= 3.5 Hz, 1H), 5.54-5.37 (m, 1H), 4.92-4.74 (s, 2H), 4.49 (br s, 1H), 4, 37 (dd, J = 2.1, 7.6 Hz, 1H), 4.19 (dd, J= 2.4, 7.3 Hz, 1H), 2.88-2.72 (m, 1H) , 2.40-2.17 (m, 3H), 2.11-1.98 (m, 1H) ppm. LC/MS: R = 1.37 min, ES<+>488 (FA standard).

Example 40: ((1S,2S,4R)-4-{4-[(3,5-Dichlorobenzyl)amino]-7/f-pyrrolo[2,3-<f]pyrimidin-7-yl}-2- hydroxycyclopentyl)methylsulfamate (compound I-16)

[0266] The title compound was prepared by following the procedure described in Example 2a-j, and 1-(3,5-dichlorophenyl)methanamine was used in step f. <!>H NMR (CD 3 OD, 400 MHz, 5): 8 .10 (s, 1H), 7.35-7.23 (m, 3H), 7.19 (d, J= 3.6 Hz, 1H), 6.58 (d, J= 3.6 Hz, 1H), 5.49-5.35 (m, 1H), 4.69 (s, 2H), 4.45 (br s, 1H), 4.33 (dd, J= 2.1, 7.6 Hz, 1H), 4.16 (dd, J=2, 4, 7.3 Hz, 1H), 2.85-2.72 (m, 1H), 2.38-2.13 (m, 3H) , 2.07-1.94 (m, 1H) ppm. LC/MS: Rt = 1.38 min, ES<+>488 (FA standard).

Example 41: [(1S,2S,4R)-2-Hydroxy-4-(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1/-

inden-1-yl]amino}-7/-pyrrolo[2,3-rf]pyrimidin-7-yl)cyclopentyl]methylsulfamate (compound 1-52)

Step a: fe/ t- Butyl [( 1 R. 2S)- 2- hydroxy- 2. 3- dihydro- l//- indene- 1 - v 1 ] carbamate

[0267] (1R,2S)-1-Aminoindan-2-ol (1.83 g, 12.3 mmol) was dissolved in DCM (70.0 mL) and TEA (3.42 mL, 24.5 mmol) was added. Di-tert-butyl dicarbonate (2.81 g, 12.9 mmol) was added at room temperature and the reaction mixture was stirred for 5 hours. The solution was concentrated in vacuo and purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexanes to give the title compound (3.12 g, 100%). LC/MS: Rt = 1.55 min, ES<+>250. (AA standard).

Step b: terf-Butyl [(1R.2S)-2-methoxy-2,3-dihydro-li/-inden-1-yl] carbamate

[0268] A mixture of tert-butyl [(1R,2S)-2-hydroxy-2,3-dihydro-1#-inden-1-yl]-carbamate (680 mg, 2.73 mmol), DMF (21 .1 mL), barium monoxide (5.02 g, 32.7 mmol), barium hydroxide (2.80 g, 16.4 mmol) and iodomethane (1.70 mL, 27.3 mmol) were stirred overnight. LC/MS showed no starting material. The reaction was quenched by the addition of a saturated solution of sodium bicarbonate and extracted with DCM. The organic layer was washed with water (3x), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes to give the title compound (178 mg, 25%). LC/MS: Rt = 1.24 min, ES<+>264 (AA standard).

Step c: (1R.2S)-2-Methoxyindan-1-amine

[0269] tert-butyl [(1R,2S)-2-methoxy-2,3-dihydro-Lf/-inden-1-yl]carbamate (253 mg, 0.961 mmol) was added to a 4.00 M solution of hydrochloric acid in 1 ,4-dioxane (5.00 mL) and the mixture was stirred for 10 min, then a white solid precipitated. The suspension was concentrated in vacuo and co-evaporated with toluene to give a white solid which was dissolved in water. The solution was adjusted to a pH of 10 by adding sodium carbonate. The mixture was then extracted with diethyl ether (3 x 30 mL) and the organic extracts were concentrated in vacuo to give the title compound (150 mg, 99%). LC/MS: Rt = 0.85 min, ES<+>164 (AA standard).

Step d: [( 1 S . 2 S . 4 R )- 2- Hydroxyl- 4-( 4-{ r( 1 R . 2 S )- 2- methoxy- 2 . 3- dihydro- 1#- inden-1-yl] - amino] - 7i/- pyrrolo [ 2, 3 - <j] pyrimidine- 7 - vl) sclopentvl] methylsulfamate

(connection 1-52)

[0270] The title compound was prepared following the procedure described in Example 2a-j, and (IR,2S)-2-methoxyindan-1-amine was used in step f.<*>H NMR (CD 3 OD, 400 MHz, 5 ): 8.20 (s, 1H), 7.27-7.14 (m, 5H), 6.67 (d, J= 3.6 Hz, 1H), 5.90 (d, J= 5, 2 Hz, 1H), 4.49 (t,J= 3.5 Hz, 1H), 4.37 (dd, J= 7.6, 9.7 Hz, 1H), 4.31-4.28 ( m, 1H), 4.20 (dd, J= 7.3, 9.7 Hz, 1H), 3.31-3.29 (m, 4H) 3.19-3.05 (m, 2H), 2.85-2.77 (m, 1H), 2.37-2.20 (m, 3H), 2.08-2.00 (m, 1H) ppm. LC/MS: Rt =1.46 min, ES<+>474 (AA standard).

Example 42: [(1S,2S,4R)-4-(4-{[(1S)-3,3-Dimethyl-2,3-dihydro-1H-inden-1-yl]amino)-7if-pyrrolo[ 2,3-<i]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate and [(1S,2S,4R)-4-(4-([(1R)-3,3-dimethyl-2,3- dihydro-L^-inden-1-yl]amino}-7if-pyrrolo[2,3-(i]pyrimidiri-7-yl)-2-hydroxycycloperityl] methylsulfamate (compound 1-14 and 1-21)

Step a: 3. 3- Dimethylindan-l- one oxime

[0271] A solution of 3,3-dimethylindan-1-ene (1.16 g, 7.21 mmol) and hydroxylamine hydrochloride (1.31 g, 18.8 mmol) in MeOH (20.0 mL) was added a solution of sodium hydroxide (765 mg, 19.1 mmol) in water (10.0 mL). The mixture was heated to 80°C for 2 hours. The cooled reaction was concentrated in vacuo and partitioned between DCM and water. The organic layer was separated and concentrated in vacuo to give the title compound as an oil (1.23 g, 97%). LC/MS: R = 1.61 min, ES<+>176 (AA standard).

Step b: 3. 3-Dimethylindan-l-amine

[0272] 3,3-Dimethylindan-1-ene oxime (1.22 g, 6.96 mmol) was dissolved in MeOH (20.0 mL) and palladium (10 wt% on carbon, 50% water wet, 148 mg) was added. The reaction was placed under a hydrogen atmosphere and stirred overnight. The mixture was then filtered through diatomaceous earth, washed with MeOH and the filtrates were concentrated in vacuo to give the product as a gray oil (1.12 g, 100%). LC/MS: Rt = 1.04 min, ES<+>162 (AA standard).

Step: r( 1S. 2S. 4R)- 4-( 4-{[( 1S)- 3. 3- Dimetvl- 2. 3- dihydro- li/- inden- 1- vl] amino1-7///- pvrrolo [ 2, 3-^] pyrimidine- 7- vl)- 2- hydroxysvclopentyl] methylsulfamate and [( 1S. 2S. 4R)- 4-( 4-{ r( 1R)- 3. 3- dimethyl- 2. 3- dihydro- li/- inden- 1-vl] amino]- 7//- pvrrolo[ 2, 3-^] pvrimidin- 7- yl)- 2-hydroxyvsvclopentvl] methylsulfamate (compound 1- 14 and 1- 21)

[0273] The title compounds were prepared by following the procedure described in la-g and then examples 2i-j, and 3,3-dimethylindan-1-amine was used in step le. The mixture was separated into its component diastereomers via chiral HPLC (Chiralpac-AS-RH, 20 mm ID x 250 mm, 5 micron column eluted with 55% water in AcCN with 0.1% AA at 6 mL/min): Peak A - 21 .4 min, [(1S,2S,4R)-4-(4-{[(1R)-3,3-dimethyl-2,3-dihydro-lif-inden-1-yl]amino)-7i7-pyrrolo [2,3-(i]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate, i?-enantiomer (compound 1-21). Peak B - 22.6 min, [(1S,2S,4R)-4-(4-{[(1S)-3,3dimethyl-2,3-dihydro-Lf/-inden-1-yl] amino }-7//- pyrrolo[2,3-tf|pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate, S-enantiomer

(compound 1-14). 'HNMR (CD 3 OD, 300 MHz, 5): 8.16 (s, 1H), 7.28-7.10 (m, 5H), 6.63 (d, J= 3.6 Hz, 1H), 5 .93 (t, J= 8.1 Hz, 1H), 5.51-5.38 (m, 1H), 4.48 (br s, 1H), 4.37 (dd, J= 7.6, 9.7 Hz, 1H), 4.20 (dd, J= 7.4, 9.6 Hz, 1H), 2.88-2.72 (m, 1H), 2.47 (dd, J= 7 ,3, 12.4 Hz, 1H), 2.37-2.19 (m, 3H), 2.03 (ddd, J= 4.5, 9.2, 13.9 Hz, 1H), 1, 93 (dd, J= 9.1, 12.3 Hz, 1H), 1.42 (s, 3H), 1.27 (s, 3H) ppm. LC/MS: R = 1.66 min, ES<+>472 (AA standard).

Example 43: [(1S,2S,4R)-4-(4-([(1S)-3,3-Dimethyl-2,3-dihydro-Lf-inden-1-yl]amino)-7// -pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate (compound 1-14), chiral synthesis

Step a: r2R)-2-(r(1S)-3.3-Dimethyl-2.3-dihydro-1/f-indene-1-v1amino1-2-phenylethanol

[0274] A solution of 3,3-dimethylindan-1-ene (925 mg, 5.77 mmol) and (R)-(-)-2-phenylglycinol (893 mg, 6.51 mmol) in two luen (10 .0 mL) was added p-toluenesulfonic acid monohydrate (62.5 mg, 0.328 mmol). The reaction was heated to reflux under a nitrogen atmosphere for 90 minutes. At this point the mixture was cooled and diluted with toluene (10.0 mL). The mixture was washed with a saturated aqueous sodium bicarbonate solution and water. The organic layer was concentrated in vacuo and the residue dissolved in THF (10.0 mL) and cooled to 0 °C. Acetic acid (1.13 mL, 19.9 mmol) was added, followed by sodium borohydride (251 mg, 6.64 mmol) and the reaction was warmed to room temperature overnight. The mixture was partitioned between DCM and the saturated aqueous sodium bicarbonate solution. The organic layer was concentrated and silica gel chromatography eluting with a gradient of 5 to 35% EtOAc in DCM afforded the title compound (1.49 g, 74%). LC/MS: Rt = 1.92 min, ES<+>282 (AA standard).

Step b: (1S)-3,3-Dimethylindan-1-amine

[0275] A solution of (2R)-2-{[(1S)-3,3-dimethyl-2,3-dihydro-Lf/-inden-1-yl]amino)-2-phenylethanol (1.44 g , 5.13 mmol) in MeOH (40.0 mL) was added to a stirred solution of lead tetraacetate (3.75 g, 8.03 mmol) in MeOH (60.0 mL) at 0 °C dropwise over 20 min . After stirring for 45 minutes, the reaction was quenched by the addition of a 10% solution of sodium carbonate in water (76.0 mL), and the mixture was stirred for 10 minutes. DCM (200 mL) was then added and the layers were separated. The aqueous layer was extracted with DCM (50.0 mL). The combined organic layers were concentrated in vacuo and the residue was dissolved in ethanol (190 mL) and treated with a 10.4 M aqueous solution of hydrochloric acid (5.70 mL, 59.3 mmol). The resulting mixture was then heated to reflux for 16 hours. The cooled reaction was concentrated in vacuo and partitioned between water (150 mL) and diethyl ether (50.0 mL). The aqueous layer was adjusted to pH 10 by addition of sodium carbonate and extracted with diethyl ether (3 x 50.0 mL). The combined organic layers were concentrated in vacuo and silica gel chromatography eluted with a gradient of 0 to 10% MeOH in DCM to give the title compound as a pale yellow oil (420 mg, 51%).<!>H NMR (CD 3 OD, 300 MHz, 5): 7.34-7.14 (m, 4H), 4.45-4.37 (m, 1H), 2.38 (dd, .7=7.1, 12.4 Hz, 1H ), 1.73 (br s, 2H), 1.60 (dd, .7= 8.7, 12.4 Hz, 1H), 1.39 (s, 3H), 1.19 (s, 3H) ppm.

Step c: [( 1S . 2S 4R )- 4-( 4-{[( 1S )- 3. 3- Dimethyl- 2. 3- dihydro- 177- indene- 1- vl1amino)-777- pyrrolo[ 2. 3 -( i]pyrimidin- 7- vl)- 2- hydroxyvsvclopentyl] methylsulfamate

(connection 1-14)

[0276] The title compound was prepared by following the procedure described in Example la-g and then Example 2i-j, and (1S)-3,3-dimethylindan-1-amine was used in step le. Chiral HPLC showed co-elution with the compound synthesized in Example 42c, peak B. Analytical data are similar to Example 42c.

Example 44: [(1S,2S,4R)-4-(4-1[(1S)-5-Chloro-2,3-dihydro-Lf-inden-1-yl]amino)-7/-

pyrrolo[2,3-(i]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate, Potassium salt (compound 1-27)

[0277] The title compound was prepared by following the procedure described in Example 43a-b and then Example 2f-j, and 5-chloroindan-1-ene was used in step 43a and (1S)-5-chloroindan-1-amine in step 2f. The potassium salt was formed by following the procedure described in Example 11. 'HNMR (CD 3 OD, 300 MHz, δ): 8.17 (s, 1H), 7.28-7.10

(m, 4H), 6.62 ( d, J= 3.6 Hz, 1H), 5.82 ( t, J= 7.7 Hz, 1H), 5.44 (qd, J= 4.6, 8.3 Hz, 1H), 4.48 (br s, 1H), 4.37 (dd, J= 7.6, 9.7 Hz, 1H), 4.19 (dd, J= 7.4, 9.7 Hz, 1H), 4.09 (q, J = 7.1 Hz, 1H), 3.05 (ddd, J= 3.3, 8.6, 15.9 Hz, 1H), 2, 98-2.71 (m, 2H), 2.64 (dtd, J= 3.5, 7.7, 11.2 Hz, 1H), 2.38-2.14 (m, 3H), 2, 05 (dd, J=4.4, 8.6 Hz, 1H) ppm. LC/MS: Rt = 1.58 min, ES<+>478 (AA standard).

Example 45: [(1S,2S,4R)-4-(4-{[(1S)-5-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-7/-

pyrrolo[2,3-(f|pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate

(compound I 36)

[0278] The title compound was prepared following the procedure described in Example 44, and 5-fluoroindan-1-ene was used. <!>H NMR (CD 3 OD, 400 MHz, 5): 8.17 (s, 1H), 7.25-7.19 (m, 2H), 6.99-6.85 (m, 2H), 6.63 (d, J= 3.6 Hz, 1H), 5.81 (t, J= 7.5 Hz, 1H), 5.49-5.41 (m, 1H), 4.49 (t, J= 3.6 Hz 1H), 4.37 (dd, J= 7.6, 9, 7 Hz, 1H), 4.20 (dd, J =7.4, 9.7 Hz, 1H), 3.12-3.02 (m, 1H), 2.95-2.87 (m, 1H ), 2.84-2.75 (m, 1H), 2.69-2.61 (m, 1H), 2.36-2.19 (m, 3H), 2.10-1.97 (m , 2H) ppm. LC/MS: R = 1.56 min, ES<+>462 (AA standard).

Example 46: [(1S,2S,4R)-4(4-{[(1S)-5-bromo-2,3-dihydro-1/-mden-1-yl]amino}-7i/-

pyrrolo[2,3-(i]pyrimidin-7-yl)-2-hydroxycyclopentyl]methylsulfamate

(connection 1-33)

[0279] The title compound was prepared following the procedure described in Example 44, and 5-bromoindan-1-ene was used. <!>H NMR (CDsOD, 400 MHz, 5): 8.17 (s, 1H), 7.42 (s, 1H), 7.29 (d, J= 8.1 Hz, 1H), 7.19-7.14 (m, 2H), 6.63 (d, J= 3.6 Hz , 1H), 5.82 (t, J= 7.8 Hz, 1H), 5.49-5.41 (m, 1H), 4.49 (br s, 1H), 4.38 (dd, J = 7.6, 9.7 Hz, 1H), 4.20 (dd, J= 7.4, 9.7 Hz, 1H), 3.08-3.01 (m, 1H), 2.96- 2.88 (m, 1H), 2.85-2.75 (m, 1H), 2.67-2.59 (m, 1H), 2.36-2.20 (m, 3H), 2, 08-1.99 (m, 2H) ppm. LC/MS: R = 1.64 min, ES<+>524 (AA standard).

Example 47: ((1S,2S,4R)-4-{4[(4-Chlorobenzyl)amino]-7H-pyrrolo[2,3-^]pyrimidin-7-yl}-2-hydroxy-2- methylcyclopentyl)methylsulfamate (compound 1-5)

Step a: ( 1 S. 5S)- 5-({[ tert-Butvl( diphenyl) silvl] oxv) metvl) sclopent- 2- en- l-ol

[0280] To a solution of (1S,5S)-5-(hydroxymethyl)cyclopent-2-en-l-ol (1.14 g, 9.99 mmol) in DCM (50.0 mL) was added TEA (4, 18 mL, 30.0 mmol) and DMAP (60.0 mg, 0.491 mmol). The solution was cooled to 0 °C, tert-butylchlorodiphenylsilane (3.90 mL, 15.0 mol) was added and the mixture was stirred at room temperature for 2 h. TLC showed complete conversion and the reaction was quenched by addition of MeOH (1.00 mL). Concentration in vacuo and silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexanes afforded the title compound (2.88 g, 86%). LC/MS: Rt = 2.51 min, ES<+>353 (AA standard).

Step b: (5S)-5-({[ter?- Butvl(diphenyl)silvl]oxv)methyl)svclopent-2-ene-1-ene

[0281 ] (1 S,5S)-5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)cyclopent-2-en-l-ol (460 mg, 1.30 mmol) was dissolved in DCM ( 15.0 mL) and pyridinium dichromate (1.47 g, 3.91 mmol) were added. The mixture was stirred at room temperature overnight, and at this

time point LC/MS showed complete conversion. The mixture was diluted with DCM (15.0 mL), filtered and concentrated in vacuo. Silica gel chromatography eluting with 0 to 50% EtOAc in hexanes afforded the title compound (400 mg, 79%). LC/MS: Rt = 2.42 min, ES<+>351 (AA standard).

Step c: ( 1S . 5S )- 5-({[ ferr?-Butyl(diphenyl)silylloxylmethyl)- 1- methylcyclopent- 2-ene-Lol

[0282] A solution of (5S)-5-({[ter?-butyl(diphenyl)silyl]oxy}methyl)cyclopent-2-ene 1-ene (250 mg, 0.713 mmol) in diethyl ether (10.0 mL) ) under a nitrogen atmosphere was cooled to -40 °C and a 1.60 M solution of methyllithium in diethyl ether (0.579 mL, 0.926 mmol) was added slowly and the mixture was stirred at -40 °C for 3 h. TLC showed complete conversion, and the reaction was quenched by addition of saturated aqueous ammonium chloride (5.00 mL), extracted with EtOAc (3 x 10.0 mL), dried over MgSO/t, filtered, and concentrated in vacuo. Silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes afforded the title compound (190 mg, 73%). Stereochemistry of the product was confirmed using ROESY analysis. LC/MS: R = 2.55 min, ES<+>367 (AA standard).

Step d: ( 1 S. 5 S )- 5-( Hydroxvmethyl)- 1 - methylcyclopent- 2- en- 1 - o 1

[0283] A solution of (1S,5S)-5-({[etr?-butyl(diphenyl)silyl]oxy}methyl)-1-methylcyclopent-2-en-l-ol (560 mg, 1.53 mmol ) in THF (29.5 mL) at 0 °C was added 1.00 M of tetra-«-butylammonium fluoride in THF (3.06 mL, 3.06 mmol). The mixture was stirred at room temperature for 2 h, then the solvent was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with a gradient of 50 to 100% EtOAc in hexanes to give the title compound (181 mg, 92%). LC/MS: Rt = 0.76 min, ES<+>129 (AA standard).

Step e: ( 1S . 2R . 3S . 5S )- 3-( Hydroxymethyl)- 2- methyl- 6- oxabicyclo[ 3. 1. 0 ] hexan- 2-ol

[0284] To a solution of (1S,5S)-5-(hydroxymethyl)-1-methylcyclopent-2-en-l-ol (0.181 g, 0.00141 mol) in DCM (18.0 mL) was added sodium bicarbonate (237 mg, 2.82 mmol), and the mixture was cooled to 0 °C. To this mixture was added 3-chloroperbenzoic acid (380 mg, 1.69 mmol), and the reaction was stirred at room temperature for 4 h. The solvent was removed in vacuo and silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in DCM afforded the title compound (200 mg, 98%). LC/MS: Rt = 0.52 min, ES<+>145 (AA standard).

Step f: (laSJbR. 5aS. 6aS)- 3-( 4- Methoxyphenyl)- 1b- methylhexahydrooxireno[ 4. 5]-cyclopenta[ 1 , 2-( f|[ 1, 3] dioxin

[0285] A solution of (1S,2R,3S,5S)-3-(hydroxymethyl)-2-methyl-6-oxabicyclo[3.1.0]hexan-2-ol (200 mg, 1.39 mmol) in DCM (13.0 mL) at 0 °C was added dimethoxy(4-methoxyphenyl)methane (0.709 mL, 4.16 mmol) followed by pyridinium p-toluenesulfonate (35.0 mg, 0.139 mmol), and the mixture was stirred at room temperature over the night. TLC showed complete conversion. Silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes afforded the title compound (215 mg, 59%). LC/MS: Rt = 1.72 min, ES<+>263 (AA standard).

Step g: (( 1S . 2S . 4R )- 4- r 4- r( 4- Chlorobenzvl)amino1- 7//- pvrrolo[ 2. 3-^ 1pyrimidine- 7-vl]- 2- hydroxysv- 2- methylsvclopentvl) methylsulfamate (compound 1-5)

[0286] The title compound was prepared by following the procedure described in example 1d-i, and (1aS,1bR,5aS,6aS)-3-(4-Methoxyphenyl)-1b-methylhexahydroxyreno[4,5]cyclopenta[1,2 -^][1,3]dioxin and 4-chlorobenzylamine were used in step d.<!>H NMR (CD 3 OD, 400 MHz, δ): 8.20 (s, 1H), 7.46 (d, J= 3.6 Hz, 1H), 7.37 (s, 4H), 6.82 (d, J= 3.6 Hz, 1H), 5.48-5.40 (m, 1H), 4.78 ( s, 2H), 4.41 (dd, J= 6.0, 10.0 Hz, 1H), 4.14 (dd, J= 8.2, 10.0 Hz, 1H), 2.69-2 .64 (m, 1H), 2.39-2.16 (m, 4H), 1.47 (s, 3H) ppm. LC/MS: Rt = 1.55 min, ES<+>466 (AA standard).

Example 48: (1S,2S,4R)-4(4-[(1S)-2,3-Dihydro-1H-mden-1-ylamino]-77H-pyrrolo[2,3-^]pyrimidine-7 -yl}-2-hydroxy-2-methylcyclopentyl)methylsulfamate

(connection 1-30)

[0287] The title compound was prepared following the procedure described in Example 47, and (S)-(+)-1-aminoindane was used in step g.<!>H NMR (CD 3 OD, 400 MHz, 5): 8, 25 (s, 1H), 7.48 (d, J= 3.6 Hz, 1H), 7.34-7.23 (m, 4H), 6.89 (d, J= 3.6 Hz, 1H ), 5.61-5.56 (m, 1H), 5.50-5.43 (m, 1H), 4.42 (dd,J=6.0, 10.0 Hz, 1H), 4, 15 (dd, J= 8.0, 10.0 Hz, 1H), 3.18-3.10 (m, 1H), 3.03-2.97 (m, 1H), 2.75-2, 64 (m, 1H), 2.39-2.07 (m, 5H), 1.48 (s, 3H) ppm. LC/MS: R = 1.57 min, ES<+>458 (AA standard).

Example 49: [(1S,2S,4R)-4-(4-([2-(difluoromethoxy)benzyl]amino}-7i/-pyrrolo[2,3-<i]pyrimidin-7-yl)-2- hydroxycyclopentyl]methylsulfamate (compound 1-2)

[0288] The title compound was prepared following the procedure described in Example 2a-j, and 2-difluoromethoxybenzylamine was used in step f.<l>H NMR (CD 3 OD, 400 MHz, 5): 8.10 (s, 1H) , 7.35-7.26 (m, 2H), 7.22 (d, J= 3.7 Hz, 1H), 7.17-7.13 (m, 2H), 6.87 (t, J = 74.2 Hz, 1H), 6.62 (d, J= 3.6 Hz, 1H), 5.45-5.20 (m, 1H), 4.80 (s, 2H), 4.49 -4.47 (m, 1H), 4.36 (dd, J= 7.6, 9.7 Hz, 1H), 4.19 (dd, J= 7.3, 9.7 Hz, 1H), 2.86-2.75 (m, 1H), 2.35-2.19 (m, 3H), 2.07-2.00 (m, 1H) ppm. LC/MS: Rt = 1.03 min, ES<+>484 (FA standard).

Example 60: (1S,2S,4R)-2-hydroxy-4-(4-{[(1R,2S)-2-isopropoxy-2,3-dihydro-li/-

inden-1-yl]-amino}-7i/-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate (compound 1-54)

[0306] The title compound was prepared following the procedure described in Example 41 a-d, and isopropyl iodide was used in step b.<*>H NMR (CD 3 OD, 400 MHz, 5): 8.20 (s, 1H), 7, 31-7.18 (m, 5H), 6.67 (d, J= 3.6 Hz, 1H), 5.82 (d, J= 5.4 Hz, 1H), 5.51-5.44 (m, 1H), 4.53-4.48 (m,2H), 4.37 (dd, J= 7.6, 9.7 Hz, 1H), 4.20 (dd, J = 7.3 , 9.7 Hz, 1H), 3.67-3.61 (m, 1H), 3.18-3.02 (m, 2H), 2.84-2.78 (m, 1H), 2, 37-2.00 (m, 4H), 1.09 (d, J= 6.1 Hz, 3H), 0.93 (d, J= 6.1 Hz, 3H). LC/MS: Rt = 1.68 min, ES<+>502 (AA standard).

Example 63: 2-((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-177-inden-1-ylamino]-7//-

pyrrolo[2,3-<i]pyrimidin-7-yl}-2-hydroxycyclopentyl)ethanesulfonamide

(connection 1-59)

Step a: 7- IYlR. 3S. 4S)- 3- tert -Butyl(Dimethyl)silyloxymethyl-4-(tert-Butyl(Dimethyl)silyloxymethyl)Sylpentyl-N-[(1S)- 2.3-Dihydro-l//-inden-1-yl]- 77^ pviTolo[ 2. 3-( i] pvrimidin- 4- amine

[0312] (1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-Lf-inden-1-ylaminol-7H-pyrrolo[2,3-(f|pyrimidine -7-yl}-2-(hydroxymethyl)cyclopentanol (0.787 g, 0.00216 mol), 17f-imidazole (0.588 g, 0.00864 mol) and N-dimethylaminopyridine (0.022 g, 0.00018 mol) were dissolved in A^TV-dimethyldanneramide (24 mL) under a nitrogen atmosphere. After 2 hours, tert-butyldimethylsilyl chloride (0.500 g, 0.00332 mol) was added, and the mixture was further stirred for 1 hour. The mixture was cooled with brine and extracted with ethyl acetate. The organic phase was evaporated and the residue was purified by silica gel chromatography, eluting with 0 to 100% ethyl acetate in dichloromethane to give 1.17g (92%) of the title compound. <!>H -NMR (300 MHz, CDCb, 5 ): 8.40 (s, 1H), 7.29 (m, 5H), 7.00 (d, 1=3.6 Hz, 1H), 6.33 (d, .7=3.3 Hz, 1H), 5.89 (dd, J =7.3 Hz, 15.3 Hz, 1H), 5.46 (ddd, J =4.3 Hz, 8.5 Hz, 18.1 Hz, 1H), 4.48 (t, J= 3.1 Hz, 1H), 3.79 (dd, J= 7.2 Hz, 9.9 Hz, 1H), 3.60 (dd, J= 6.8 Hz, 9.9 Hz, 1H), 3.00 (m, 1H), 2.75 (dt d, J=4.0 Hz, 7.6 Hz, 11.7 Hz, 1H), 2.45 (d, .7=4.0 Hz, 1H), 2.22 (d, .7=4, 0 Hz, 3H), 1.96 (d, .7=4.0 Hz, 2H), 0.90 (s, 18H), 0.08 (s, 12H).

Step b: r( 1S. 2S. 4R)- 24te^ butyl( dimetvnsilvl1oxv- 4- r4- rriS)- 2. 3- dihydro- LF/-inden- 1- vlaminol- 7//- pyrrolo[ 2, 3- (/1pvirimidin-7-vl}svclopentalN)methanol

[0313] 7-[(1R,3S,4S)-3-[tert-butyl(dimethyl)silyl]oxy-4-([tert-butyl(dimethyl)silyl]-oxymethyl)cyclopentyl]-7V-[( 1 S)-2,3-dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-tf|pyrimidin-4amine (1.66 g, 0.00280 mol) was dissolved in a mixture of tetrahydrofuran ( 6.6 mL), water (6.6 mL, 0.36 mol) and acetic acid (19 mL, 0.34 mol). The solution was then heated to 40 °C overnight. The mixture was then cooled and evaporated, azeotroped with toluene (2 x 50 mL) and the residue was purified by silica gel chromatography eluting with 0 to 100% ethyl acetate in dichloromethane to give the product as a white solid, 1.05g (74%) . LC/MS: Rt = 1.68 min, ES<+>479 (AA standard).

Step: ( 1R. 2S. 4R)- 2- rtetr- butvl( dimetvl) silvl1oxv- 4-{ 4-[( 1S)- 2. 3- dihvdro- li/-inden- 1- vlamino]- 7//- pyrrolo[2,3-6ripvrimidin-7-yl]cyclopentanecarbaldehyde

[0314] ((1 S ,2 S ,4 R )-2- [tetra-butyl(dimethyl)silyl] oxy-4- {4- [(1 S )-2,3-dihydro-1 H -inden-1 -ylamino]-7H-pyrrolo[2,3-^]pyrimidin-7-yl}cyclopentyl)methanol (257.0 mg, 0.0005369 mol) was dissolved in methylene chloride (10.0 mL) under argon. 7V-Methylmorpholine N-oxide (126 mg, 0.00107 mol), and 4Å molecular sieves (250 mg, freshly flame dried) were then added and the mixture was stirred for 10 min at room temperature. Tetrapropylammonium perrutenateVII (18.9 mg, 0.0000537 mol) was then added and the resulting dark green solution was stirred for 1 hour at room temperature. The reaction mixture was filtered through a plug of silica gel, washed with DCM (20 mL), followed by 50% ethyl acetate in DCM (150 mL). The eluate was evaporated to give the product as a clear light green oil. The residual concentration was transferred to the next reaction without further cleaning.

Step d: Ethyl ( E )- 2 (( 1S . 2S . 4R )- 2- rte^ buM( dimethyl ) silylloxv- 4-{ 4- r( 1S )- 2. 3-dihydro- 1//- indene- 1 - vlamino]- 7i/- pviTolo[ 2. 3-( i] pvirimidine- 7-scyclopentyDethylenesulfonate

[0315] A stirred solution of (diethoxy-phosphoryl)-methanesulfonic acid ethyl ester (285 mg, 0.00110 mol) in tetrahydrofuran (5.0 mL) was added dropwise, 2.5 M with n-butyllithium in hexane (440 uL, 0.00110 mol) at -78 °C under a nitrogen atmosphere. The mixture was then stirred for 30 minutes. To this solution was added dropwise a solution consisting of (1R,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(15)-2,3-dihydro-l/ -inden-l-ylamino]-7//-pyrrolo[2,3-^]pyrimidin-7-yl}cyclopentanecarbaldehyde (212.0 mg, 0.0004447 mol) in tetrahydrofuran (5.0 mL) at -78 ° C. The resulting pink solution was stirred for 1.5 h at -78 °C. The reaction mixture was heated and cooled by the addition of saturated NH 4 Cl (30 mL). The resulting mixture was extracted with DCM (3 x 30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with 30 to 50% ethyl acetate in hexane to give the product as a colorless oil, 132 mg (51%). LC/MS: Rt = 2.55 min, ES<+>583 (AA standard).

Step e: Ethyl 2- rnS. 2S. 4R)- 2- tert-butyl(dimethylsilyl1oxv- 4-[ 4-[ nS)- 2. 3-dihydro- li/- inden- 1- vlamino]- 7i/- pvrrolo[ 2. 3-( i] pvrimidin- 7-

howl| svklopentvDetansulfonate

[0316] Ethyl-2-((1S,2S,4R)-2-[tetra-butyl(dimethyl)silyl]oxy-4-(4-[(1S)-2,3-dihydro-1H-inden -1-ylamino]-7 H -pyrrolo[2,3-fr]pyrimidin-7-yl}cyclopentyl)ethylene sulfonate (132.0 mg, 0.0002265 mol) was dissolved in ethanol (8.0 mL) and sodium borohydride ( 42.8 mg, 0.00113 mol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was cooled with NH 4 Cl solution, and the mixture was concentrated to remove the ethanol. The aqueous residue was then extracted with dichloromethane, and the organic phase was concentrated. The residue was purified by silica gel chromatography 15% ethyl acetate in dichloromethane to give the product, 92 mg (69%). LC/MS: Rt = 2.51 min, ES<+>585 (AA standard).

Step f: 7V, A^, 7V- tributylbutane- 1- aminium- 2-(( 1S. 2S. 4R)- 2- tert-butyl( dimetvl) silvl1oxv- 4- r4- r( 1S)- 23- dihydro- lif-inden-1-ylamino1-7if-pvrrolo[2,3-(f1pvirimidin-7-vl]svclopentyl)ethanesulfonate

[0317] Ethyl 2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-indene -1-ylamino]-7 H -pyrrolo[2,3-(f]pyrimidin-7-yl]cyclopentyl)ethanesulfonate (92 mg, 0.0001573 mol) and tetra-n-butylammonium iodide (62.0 mg, 0 .000168 mol) was dissolved in acetone (2.5 mL, 0.034 mol) and the mixture was heated using microwave irradiation at 140 °C for 70 seconds. The cooled reaction mixture was concentrated to dryness to give the crude product, 140 mg. LC /MS: Rt =1.75min, ES<+>557 (AA standard).

Step: 2-(( 1S . 2S . 4R )- 2-[ ethrt-butyl( dimethylsilvyl 1oxv- 4[ 4- r( 1S )- 23- dihydro- 1//-inden- 1- ylamino]- 7//- pvrrolo[ 2, 3- 6ripvrimidin-7-yl] svclopentvDetanesulfonamide

[0318] 7V,AWributylbutane-1-aminium 2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro -1H-inden-1-ylamino]-7H-pyrrolo[2,3-tf|pyrimidin-7-yl)cyclopentyl)ethanesulfonate (66.0 mg, 0.0000744 mol) was dissolved in methylene chloride (2 .0 mL, 0.031 mol) and A^A^-dimethyldanneramide (5.50 uL, 0.0000710 mol) were added. The mixture was cooled to 0 °C and thionyl chloride (50.0 µL, 0.000685 mol) was added dropwise. The reaction was stirred at 0 °C for 2.5 hours. The reaction mixture was diluted with toluene and concentrated to dryness. The residual concentration was again azeotroped with toluene. The residue was washed down a silica pad (-3 g) with 0 to 10% THF/DCM to give the acid chloride intermediate, 42 mg. The acid chloride was taken up in a 0.500 M solution of ammonia in 1,4-dioxane (5.00 mL) and the resulting solution was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was then evaporated and the residual concentration was partitioned between DCM and water. The organic phase was evaporated to give the crude product, 35 mg (85%). LC/MS: Rt =1.64 min, ES<+>556 (AA standard).

Step h: 2-(( 1S. 2S. 4R)- 4- r4- r( 1S)- 2. 3- dihydro- 1//- inden- 1- ylamino1- 7//pyrrolo[ 2, 3-(/ 1-pyrimidine-7-vll-2-hydroxyvsvclopentyl)ethanesulfonamide

(connection 1-59)

[0319] 2-((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden- 1-ylamino]-7/-pyrrolo[2,3-(/]pyrimidin-7-yl)cyclopentyl)ethanesulfonamide (32 mg, 0.000057 mol) was dissolved in tetrahydrofuran (1.0 mL, 0.012 mol) and a 1.00 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (0.100 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled with a little water and then concentrated. Purification of the residue by silica gel chromatography eluting with 0 to 100% of (9:1EtOAc:EtOH) in DCM afforded the desired product, (9 mg, 40%).<*>H -NMR (400 MHz, MeOD, 5): 8.16 (s, 1H), 7.19 (m, 5H), 6.62 (d, J= 3.6 Hz, 1H), 5.85 (t, J=l .7 Hz, 1H), 5.43 (dddd, J= 4.2 Hz, 8.4 Hz, 8.4 Hz, 8.4 Hz, 1H), 4.35 (t, J= 3.7 Hz, 1H), 3.13 (m, 3H), 2.91 (m, 1H), 2.63 (m, 1H), 2.49 (m, 1H), 2.35 (ddd, J= 1.2 Hz, 8 .1 Hz, 13.8 Hz, 1H), 2.05 (m, 6H). LC/MS: Rt = 1.07 min, ES<+>442 (AA standard).

Example 65: N-[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-

pyrrolo[2,3-tf|-pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl]sulfamide

(connection 1-56)

Step a: tert-butyl (aminosulfonyl)[(Y1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2.3-dihydro - 1/ 7- inden- 1- vlamino]- 7i/- pvrrolo[ 2, 3-(/ 1pvrimidin-7yl-] cyclopentyl) methyl] carbamate

[0323] ((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-Lf-indenylamino]-7i /-pyrrolo[2,3-(i]pyrimidin-7-yl}cyclopentyl)methanol (700.0 mg, 0.001462 mol), N-Boc-sulfonamide (398 mg, 0.00203 mol) and triphenylphosphine (575 mg, 0.00219 mol) was dissolved in ethyl acetate (28 mL, 0.28 mol) at 50 °C under a nitrogen atmosphere. Diethyl azodicarboxylate (350.0 uL, 0.002223 mol) was added over 2-3 minutes and the mixture was stirred at 50° C. for 30 min. The cooled mixture was evaporated and the residue purified by silica gel chromatography, eluting with 10 to 100% ethyl acetate in hexanes to give the product as a white solid, 636 mg (66%). LC /MS: Rt = 2.55 min, ES<+>657 (AA standard).

Step b: tert-butyl (aminosulfonyl)rrriS. 2S. 4R)- 4{ 4- r( 1S)- 2. 3- dihydro- ljy- inden- l-ylamino] - 7if- pvrrolo[ 2. 3-^] pvrimidin- 7- vl- 2-hydroxyvsvclopentyl) metvl] carbamate

[0324] tert-Butyl (aminosulfonyl)[((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-4-[(1S)-2,3-dihydro-1/ -inden-1 -ylamino]-7/f-pyrrolo[2,3-<i]pyrimidin-7-yl}cyclopentyl)methyl]carbamate (457 mg, 0.000696 mol) was dissolved in tetrahydrofuran (10.0 mL ), 1.00 M aqueous hydrochloric acid (10.0 mL) and ethanol (10.0 mL). The mixture was stirred at room temperature overnight. Sodium bicarbonate (842 mg, 0.0100 mol) was added to the mixture, followed by water (10 mL). The mixture was then concentrated to -20 mL volume, and this aqueous residue was extracted with EtOAc (2 x 50 mL). The separated organics were concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 100% ethyl acetate to give the product, 362 mg (96%). LC/MS: Rt = 1.77min, ES<+>543 (AA standard).

Step C: 7V-[ r( 1S. 2S. 4R)- 4-{ 4-[( 1S)- 2. 3- dihydro- li/- inden- 1- vlamino1- 7i/pvrrolo] 2. 3-^ 1pvrimidine - 7-(v)-2-hydroxyvsvclopentyl)methyl]sulfamide

(connection 1-56)

[0325] tert-Butyl (aminosulfonyl)[((1S,2S,4R)-4[4-[(1S)-2,3-dihydro-Lf/-inden-1-ylamino]-7i/-pyrrolo[2 ,3-tf|pyrimidin-7-yl]-2-hydroxycyclopentyl)methyl]carbamate (345 mg, 0.000636 mol) was dissolved in 2:1 methylene chloride:trifluoroacetic acid (20 mL:10 mL) and allowed to stand for 15 minutes at room temperature. The mixture was diluted with toluene (30 mL) and evaporated to dryness. The residue was then again subjected to the same conditions and azeotroped with toluene after completion. The residue was purified by silica gel chromatography, eluting with 5 to 10% methanol in dichloromethane to give the product, 135 mg (48%). <!>H -NMR (400 MHz, MeOD) δ 8.16 (s, 1H) , 7.19 (m, 5H), 6.62 (d, 7=3.6 Hz, 1H), 5.85 (t, 7=7.8 Hz, 1H) 5.43 (ddd, 7 =4 .6 Hz, 8.5 Hz, 17.8 Hz, 1H), 4.46 (t, 7=3.6 Hz, 1H), 3.15 (dd, 7=7.1 Hz, 12.9 Hz , 1H), 3.05 (ddd, 7=3.3 Hz, 8.7 Hz, 15.4 Hz, 1H), 2.91 (m, 1H), 2.63 (m, 1H), 2, 33 (ddd, 7=1.5 Hz, 8.0 Hz, 13.8 Hz, 1H), 2.20 (m, 2H), 2.02 (m, 2H). LC/MS: Rt =1.45min, ES<+>443 (AA standard).

Example 69: Enzyme production

[0348] All protein accession numbers provided herein refer to the Entrez Protein database maintained by the National Center for Biotechnology Information (NCBI), Bethesda, MD.

Generation of E-enzymes

[0349] According to manufacturer instructions, baculoviruses were generated with the "Bac-to-Bac Expression System" (Invitrogen) for the following proteins: untagged NAEa (APPBP1, NP_003896.1), N-terminally His-tagged NAEB (UBE1C, NP_003959.3) , untagged SAEa (SAE1, NP 005491.1), N-terminal His-tagged SAEB (UBA2, NP_005490.1), N-terminal His-tagged murine UAE (UBE1X, NP_033483). NAEa/His-NAEB and SAEa/His-SAE(3 complexes were generated through co-infection of S/9 cells which were harvested after 48 h. His-mUAE was generated through a single infection of S/9 cells and harvested after 72 h Expressed proteins were purified through affinity chromatography (Ni-NTA agarose, Qiagen) using standard buffers.

Generation of E2 enzymes

[0350] Ubcl2 (UBE2M, NP_003960.1), Ubc9 (UBE2I, NP.003336.1), Ubc2 (UBE2A, NP.003327.2) were subcloned into pGEX (Pharmacia) and expressed as N-terminally GST-tagged fusion proteins in E. coli . Expressed proteins were purified through conventional affinity chromatography using standard buffers.

Generation of Ubl proteins

[0351] Nedd8 (NP 006147), Sumo-1(NP_003343) and Ubiquitin (with optimized codons) were subcloned into pFLAG-2 (Sigma) and expressed as N-terminally Flag-tagged fusion proteins in E.coli. Expressed proteins were purified by conventional chromatography using standard buffers.

Example 70: E-enzyme assays.

Nedd8-activating enzyme (NAE) HTRF assay.

[0352] The NAE enzymatic reactions were a total of 50 uL and contained 50 mM HEPES (pH 7.5), 0.05% BSA, 5 mM MgCk, 20 uM ATP, 250 uM GSH, 0.01 uM Ubcl2-GST, 0.075 pM Nedd8 Flag and 0.28 nM recombinant human NAE enzyme. The enzymatic reaction mixture, with and without binding inhibitor, was incubated at 24 °C for 90 min in a 384-well dish before disruption with 25 µL of stop/detect buffer (0.1 M HEPES pH 7.5, 0.05% Tween20, 20 mM EDTA, 410 mM KF, 0.53 nM Europium-Cryptate-labeled monoclonal anti-FLAG M2 antibody (CisBio International) and 8.125 ug/mL PHYCOLINK goat anti-GST allophycocyanin (XL-APC) antibody (Prozyme)). After incubation for 3 h at 24 °C, quantification of FRET was performed on Analyst™ HT 96.384 (Molecular Devices).

[0353] Compounds I-1 to 1-54, 1-56 and 1-59 exhibited IC 50 values less than or equal to 10 µM in this assay. Compounds I-1, 1-2,1-3,1-4,1-6,1-7,1-8,1-12,1-13,1-14,1-15,1-16,1-17 ,1-18,1-19,1-21,1-22,1-23,1-24,1-25,1-26,1-27,1-28,1-29,1-30, 1 -31,1-32,1-33,1-34,1-35,1-36,1-37,1-38,1-39,1-40,1-41,1-42,1-43 ,1-45,1-46,1-47,1- 48,1-49,1-50,1-51,1-52,1-54,1-56 and 1-59 displayed ICS values less than or corresponding to 100 nM in this assay.

Sumo-activating enzyme (SAE) HTRF assay.

[0354] The SAE enzymatic reaction was performed as listed above for NAE except that Ubcl2-GST and Nedd8-Flag were replaced with 0.01 uM Ubc9-GST and 0.125 uM Sumo-Flag respectively and the concentration of ATP was 0.5 uM. Recombinant human SAE (0.11 nM) was the enzyme source.

Ubiquitin-activating enzyme (UAE) HTRF assay.

[0355] The UAE enzymatic reaction was performed as listed above for NAE except that Ubcl2-GST and Nedd8 Flag were replaced with 0.005 µM Ubc2-GST and 0.125 µM Ubiquitin Flag, respectively, and the concentration of ATP was 0.1 µM. Recombinant mouse UAE (0.3 nM) was the enzyme source.

Example 71: Cell analyses

[0356] Selected compounds associated with formula (I) were tested in cell assays:

Anti-proliferation assay (WST)

[0357] Calu-6 (2400/well) or other tumor cells in 80 uL of appropriate cell culture medium (MEM for Calu6, Invitrogen) supplemented with 10% fetal bovine serum (Invitrogen) were seeded into wells of a 96-well cell culture dish and incubated for 24 hours in a tissue culture incubator. Binding inhibitors were added in 20 µL of culture medium to the wells and the dishes were incubated for 72 hours at 37 °C. 10% final concentration of WST-1 reagent (Roche) was added to each well and incubated for 3.5 h (for Calu6) at 37 °C. The optical density of each well was read at 450 nm using a spectrophotometer (Molecular Devices). Percent inhibition was calculated using the values from a DMSO control set to 100% viability.

Anti-proliferation assay (ATPLite)

[0358] Calu-6 (1500 cells/well) or other tumor cells were seeded in 72 uL of appropriate cell culture medium (MEM for Calu6, Invitrogen) supplemented with 10% fetal bovine serum (Invitrogen) in wells belonging to a 384-well Poly-D-Lysin -coated cell culture plate. The splicing inhibitors were added in 8 µL of 10% DMSO/PBS to the wells and the dishes were incubated for 72 hours at 37°C. The cell culture medium was aspirated leaving 25 uL in each well. 25 µL of ATP lite 1 step™ reagent (Perkin Eimer) was added to each well. The luminescence for each well was read using the LeadSeeker Microplate Reader (Molecular Devices). Percent inhibition was calculated from a DMSO control set at 100% viability.

Example 72: In Vivo Assays

[0359] Selected compounds associated with formula (I) were tested in in vivo assays.

In vivo tumor efficacy model

[0360] Calu6 (5 x 10<6> cells), HCT116 (2 x 10<6> cells) or other tumor cells in 100 uL of phosphate buffered saline were aseptically injected into a subcutaneous area in the right dorsal flank of a female Ner nude mouse (5-8 weeks old, Charles River) using a 26-gauge needle. Beginning on day 7 post-vaccination, tumors were measured twice a week using a caliper. Tumor volumes were calculated using standard procedures (0.5 x (length x width<2>)). When the tumors reached a volume of approx. 200 mm<3> mice were randomized into groups and injected intravenously in the tail vein with compound inhibitors (100 uL) at different doses and schedules. As another alternative, compound inhibitors can be administered to mice by intraperitoneal or subcutaneous injection or oral administration. All control groups received only the binder. Tumor size and body weight were measured twice per week and the study ended when the control tumors reached approx. 2000 mm<3>.

[0361] Patent and scientific literature referenced herein establish knowledge available to those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art to which this invention pertains.

[0362] Although a number of embodiments associated with this invention have been described, it is apparent that the basic examples provided may be modified to show other embodiments using the compounds and methods associated with this invention. It will therefore be understood that the scope of this invention is shown here through examples and is defined by the appended claims.

Claims (8)

1. Compound with formula (I): or a pharmaceutically acceptable salt thereof wherein: stereochemical configurations depicted at positions with asterisks show relative stereochemistry, ring A is selected from the group consisting of: where one ring nitrogen atom in ring A is optionally oxidized, X is -O-, Y is -CH2-, Ra is hydrogen or OH, R<b>is hydrogen, fluoro or Ci-4 aliphatic group, R° is hydrogen, fluoro or OH Rd is hydrogen, fluoro or Ci-4 aliphatic group, Re is hydrogen or C1-4 aliphatic group, Re is hydrogen, each Rf is hydrogen, R<g>is hydrogen, halogen, -OR<5>, -SR<6>, -N(R<4>)2, -NR<4>C(0)R<5>or an optionally substituted aliphatic group, each Rh is hydrogen, Rj is hydrogen, R<k>is hydrogen or halogen, each R<4> is independently hydrogen or an optionally substituted aliphatic, aryl, heteroaryl or heterocyclyl group, each R<5> is independently hydrogen or an optionally substituted aliphatic, aryl, heteroaryl or heterocyclyl group, each R<6> is individually an optionally substituted aliphatic, aryl or heteroaryl group, and m is 1, and where the optional substituent is halogen, C1-4aliphatic group, C1-4alkyl, C1-4halogenaliphatic group, C1-4halogenalkoxy, phenyl, or phenyl substituted with halogen, C1-4aliphatic group, C1-4alkyl, C1-4halogenaliphatic group, C1-4 4halogenoalkyl. 2. Compound in claim 1 characterized by the following properties (a) X is -O-, (b) Y is -CH2-, (c) Ra is -OH, (d) R<b>and Rd are hydrogen, (e ) R<c>is hydrogen, (f) Re and Re are each hydrogen, (g) each Rf is hydrogen, (h) each Rh is hydrogen, (i) Rj is hydrogen, (j) R<k>is hydrogen , (k) m is 1, and (1) stereochemical configurations depicted as positions with asterisks show absolute stereochemistry. 3. Compound in claim 1 characterized by formula (VII): or a pharmaceutically acceptable salt thereof wherein: Q is =N or =C(R<k>)- where R<k> is hydrogen, R<8> is hydrogen or C 1-4 aliphate, and ring D is optional, a substituted mono-, bi- or tricyclic ring system wherein ring D is selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl, purinyl, quinolyl, isoquinolyl, quinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, quinuclidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, penanthridinyl, tetrahydronaphthyl, indolinyl, benzodioxanyl, cromanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclope ntenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, bicycloheptanyl and bicyclooctanyl, and where the optional substituent is halogen, C 1-4 aliphatic group, C 1-4 alkoxy, C 1-4 haloaliphatic group, C 1-4 or halogeno alkoxy. 4. Compound in claim 3 wherein ring D is optionally a substituted indanyl, tetrahydronaphthyl or chromanyl. 5. Compound in claim 4 where: ring D is selected from the group consisting of: each R<p>which is individually selected from the group consisting of halogen, -OR<5x>and a C1-4 aliphatic group, each R<8p>which is individually selected from the group consisting of fluoro, -OR<5x>, and a C1-4 aliphatic group, provided that R<8P> is other than -OR<5x> when located at a position adjacent to a ring oxygen atom and provided further that when two R<8P>s are attached to the same carbon atom, one must be selected from the group which consists of fluoro, each R<5x>is optionally hydrogen or C1-4alkyl, serO, 1,2,3 or 4, t is 0, 1 or 2. 6. Compound in claim 5 characterized by formula (Villa): or a pharmaceutically acceptable salt thereof wherein: Ra is -OH, R<b>and Rd is hydrogen, R° is hydrogen, fluoro or OH, R<8>is hydrogen, Q is =N- or =C(R< k>) where R<k>is hydrogen, each R<p>is individually selected from the group consisting of fluoro and -OR<5x>, each R<8p>individually selected from the group consisting of fluoro and -OR<5x>, each R<5x> individually is hydrogen and C1-4 aliphatic group, s is 0, 1 or 2, and t is 0, 1 or 2. 7. Compound according to claim 1, wherein the compound is 8. A compound according to claim 1 which is or a pharmaceutically acceptable salt thereof.